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Histone Modifications and their Role in Colorectal Cancer (Review)

Histone Modifications and their Role in Colorectal Cancer (Review) The development of colorectal cancer is a complex and multistep process mediated by a variety of factors including the dysregulation of genetic and epigenetic under the influence of microenvironment. It is evident that epigenetics that affects gene activity and expression has been recognized as a critical role in the carcinogenesis. Aside from DNA methylation, miRNA level, and genomic imprinting, histone modification is increasingly recognized as an essential mechanism underlying the occurrence and development of colorectal cancer. Aberrant regulation of histone modification like acetylation, methylation and phosphor- ylation levels on specific residues is implicated in a wide spectrum of cancers, including colorectal cancer. In addition, as this process is reversible and accompanied by a plethora of deregulated enzymes, inhibiting those histone-modifying enzymes activity and regulating its level has been thought of as a potential path for tumor therapy. This review provides insight into the basic information of histone modification and its application in the colorectal cancer treatment, thereby offering new potential targets for treatment of colorectal cancer. . . . . Keywords Histone modification Colorectal cancer Histone acetylation Histone methylation Histone phosphorylation Introduction regulatory mechanisms of epigenetics, which is detected pri- marily in the amino- and carboxy-terminal histone tails. It is The accumulation of genetic and epigenetic dysregulation are also an important mechanism in cancer progression [4]. In this two kinds of separate mechanisms which resulted in tumori- setting, a variety of cancer such as gastric cancer, prostate genesis. Genetic variations have traditionally been regarded as cancer, lung cancer, et al. have been extensively reported to an important player in the occurrence and development of the be correlated with this change [5–7]. Colorectal cancer (CRC) tumor. Nevertheless, current data have been accumulating is a multi-factorial disease and retains its status as the most concerning the epigenetic change which is responsible for common cause of cancer-related death, with more than the genesis and progression of cancer [1]. epigenetics is de- 6000,000 estimated death across the globe every year [8]. fined as the study of changes in the expression and regulation The etiology of colorectal cancer is not completely of genes does not involved in changes in the DNA sequence established, accordingly, it is critical to probe into the molec- which can be classified into DNA methylation, histone mod- ular bases of colorectal cancer and markers for the early diag- ification, miRNA, genomic imprinting and chromosome re- nosis and treatment of this cancer. Aberration in histone mod- modeling [2, 3]. Up to now, DNA methylation and histone ification may become an early diagnosis of colorectal cancer. modification are the most intensively studied epigenetics; This review focus on understanding the role of histone mod- Moreover, Histone modification is one of the important ifications in the progression of colorectal cancer and their application in colorectal cancer may provide a new direction for diagnosis, treatment,and prognosis of colorectal cancer. * Bin Wen wenbin@gzucm.edu.cn Histone Modification Institute of Spleen and Stomach, Guangzhou University of Chinese Medicine, Guangzhou 510000, China Chromatin is a dynamic molecule with multiple structures and there are two basic forms: heterochromatin and euchromatin. Lianyungang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China Epigenetic events are essential to regulate the condensation 2024 J. Qin et al. state of chromatin and hence to regulate the function of ge- modifications of histone lie in inappropriate targeting of nome by means of histone modifications, chromatin remodel- histone-modifying enzymes, including HATs, HDACs, ing, DNA methylation and no-coding RNA [9] Fig. 1. the HMTs, and HDMTS, locally at gene promoters, resulting in fundamental unit of chromatin is nucleosome, which is com- perturbations or mutations in genes [17]. posed of two copies of histones H2A, H2B, H3, and H4, wrapping with approximately 147 base pairs of DNA [10]. Histone Acetylation Histone, one of the major components of chromatin, has long tails protruding away from the nucleosome, which is suscep- Reversible histone acetylation is a dynamic process that is tible to covalently modified at several places [11]. It includes achieved by the addition or removal of histone acetyltransfer- many kinds of covalent modifications, such as acetylation, ases (HATs) and deacetylases (HDACs) [18]. In recent years, phosphorylation, methylation, ubiquitylation, sumoylation the HATs that has been identified mainly includes P300/CBP, and so on [12]. At present, more efforts have been put into GNAT, MYST, P160, PCAF, TAFII230 families [19]. In the two aspects of histone modification namely, acetylation, meth- higher eukaryotes, HDACs can be classified into four groups ylation in terms of the orchestration chromatin structure and on the basis of their homology with the original yeast enzyme gene expression [13, 14]. The combination of single or multi- sequence. Class I HDACs, including HDAC1, 2, 3, 8; Class II histone modification can interact with each other which forms HDACs composed of HDAC4, 5, 6, 7, 9, 10; Class III Bhistone modification code^ [15]. Covalent modification of HDACs, also known as Sirtuins, comprised of SIRT1–7; histones can change the nucleosomal conformation in such a Class IV HDACs, including HDAC11 [20]. Among these way that modulate the chromatin structure and expression of HDACs Class I, II and IV are zinc-dependent, while Class genes [16]. currently, an emerging role of aberrant histone III are NAD -dependent. HATs transfer the acetyl group of modifications have been found in a wide spectrum of cancer, acetyl coenzyme A to the terminal of histone amino acid and giving rise to the role of histone modification is under exten- relax the structure of chromatin under the action of electric sively investigation [13]. The reason why these aberrant charge, which is helpful to transcription by means of Fig. 1 Epigenetics regulate the gene expression without alteration in the setting of colorectal cancer such as acetylation, methylation, and DNA sequence. It mainly consists of DNA methylation, histone phosphorylation. This process is mediated by HATs, HDACs, HMTs, modification, non-coding RNA, chromatin remodeling. a The HDMs and protein kinases (PKs). In open chromatin state, histone tail protruding of amino tails of histone modification can undergo several recruits HATs, HMTs, and PKs which can promote gene transcription. In post-translational modifications that affect the expression of genes. closed chromatin state, histone tail removes these histone-modifying Illustrated is the major histone modifications that have been studied in enzymes which can inhibit the gene transcription. (b) Histone Modifications and their Role in Colorectal Cancer (Review) 2025 increasing the accessibility of DNA. On the contrary, HDAC H3K79 [25]. In addition to the histone methyltransferase, removes the terminal acetyl group of histone lysine making the finding of HDMTs by Shi et al., making the process of the structure of chromatin is compact which result in the inhi- histone methylation more dynamic [26]. From then on, a va- bition of transcription [21]. In generally, hyperacetylation riety of HDMTs has been observed, such as LSD1, UTX, leads to the increased expression of the gene which is related JMJD3, JMJD1A. In contrast to histone acetylation that pro- to the activation of gene transcription, while hypoacetylation motes gene expression, histone lysine methylation has a more means repression of gene expression [22]. complicated effect on gene expression which is depending on the location of modified residues being methylated lead to either transcriptionally-active or -repressive. For instance, Histone Methylation methylation at H3K4 and H3K36 sites activate gene transcrip- tion. Conversely, methylation at H3K9, H3K27, H3K79, Histone methylation refers to the transfer of methyl group to H4K20 sites inhibits gene transcription [27]. the residues of histone arginine or lysine by taking S- adenosylmethionine as methyl donor under the action of his- tone methyltransferases (HMTs). Similar to histone acetyla- Histone Phosphorylation tion, histone methylation is also a dynamic event which is regulated by different types of HMTs and histone Histone phosphorylation, taking place mainly at serines (S), demethytransferases (HDMTs). Histone methylation predom- threonines (T) and tyrosine (Y) residues of histone tails, is one inantly occurs in arginine and lysine residues of histone tails of the histone modifications. Phosphorylation disrupts the in- and is catalyzed by HMTs. Lysine can be monomethylated, teraction between histones and DNA attributed to the instabil- dimethylated or trimethylated, respectively, arginine is either ity of chromatin structure which is requirement for the struc- monomethylated or dimethylated. Furthermore, Lysine meth- tural recombination of chromatin agglutination into homolo- ylation is a more stable and complex modification of gene gous chromosomes during mitosis. It matters that different expression regulation, which occurs mainly on histone H3 types of the phosphorylated site within histone is intimately and H4. There are six sites of lysine methylation that have linked to different chromatin functions. Moreover, Histone been extensively studied such as H3K9, H3K27, H3K36, phosphorylation together with other modifications such as H3K79, and H4K20 [23](Table 1). Protein arginine methyl- histone acetylation is involved in gene transcription, DNA ation is chiefly catalyzed by some members of the protein repair, apoptosis and chromosome condensation. For instance, arginine methyltransferase family including PRMT1, ChIP sequencing data manifested that histone H3 phosphory- PRMT3, PRMT1/HMTA, PRMT4/CARMA, PRMT5 [24]. lated at tyrosine 41 (H3Y41) presents in transcriptional start HMTs comprised of histone arginine methyltransferase sites (TSS) function together with H3K4me3 which implicat- (PRMTs) and histone lysine methyltransferase (HKMTs). ed in transcriptional activation [28]. Furthermore, the combi- PRMTs can be classified as two types: Type I catalyzes the nation of H3Y41 and H3K56 function together can signifi- formation of mono-methylarginine and asymmetric di- cantly increase the accessibility of DNA by more than an order methylarginine; Type II catalyzes the formation of of magnitude [29]. Histone H3 phosphorylated at threo- monomethyl arginine and symmetric di-methylarginine. nines45 (H3T45) takes part in apoptosis and DNA replication HKMTs mainly include Suv39h1, Suv39h2, G9a, EZH2, and can promote the acetylation of H3K56 [30, 31]. There is SET1, SET2, SET9 which contains the SET domain. various kinase responsible for phosphorylation such as Aurora DOT1L is the only lysine methyltransferase without the SET kinase(AKs), protein kinase B (PKB/Akt), cyclin-dependent domain, which can specifically catalyze the methylation of kinases (CDKs), protein kinase C (PKC), casein kinase 2 Table 1 Classification of histone Class Members methyltransferases and demethyltransferases HMTs PRMTs Type I PRM1, PRM3, PMT1/HMT, PRMT4/CAMR1 Type II PRMT5 HKMTs Type I G9a, EZH2, Suv39h1, Suv39h2, SET1, SET2, KMT2A Type II DOTL1 HDMs LSD1, UTX, JMJD3, JMJD1A Adapted from Ref. [23] PRMTs type I: mono-methylarginine and asymmetric dimethylargine; PRMTs type II: mono-methylarginine and symmeric dimethylarginine; HKMTs type I: lysine-specific SET histone transferases; HMTs type II: without lysine SET histone transferases 2026 J. Qin et al. (Ck2) and Rad3 related kinase ATR [32], and so on. H3Y41 is Histone Acetylation and Colorectal Cancer catalyzedbyJAK2 tyrosinekinase(JAK2) [33]. Bub1 is the kinase responsible for phosphorylation of H2AT120 and Up to now, it has been the overwhelming accumulation of H3T3 phosphorylated by Haspin kinase [34, 35]. evidence indicated that histone acetylation finely regulates a wide range of cell functions, such as cell differentiation, as- sembly of the nucleosome, the change of chromatin structure and stability of gene expression [43]. it’s not surprising that Histone Modification and Colorectal Cancer abnormal regulation of histone acetylation is relevance to the predisposition to developing colorectal cancer and this pro- Given that previous research on histone modification in the de- cess is modulated by a plethora of deregulated enzymes in- velopment of colorectal cancer, the relationship between histone cluding HATs, HDATs. Karczmarski et al. used both mass modification and colorectal cancer have been evolving under- spectrometry (MS) and western blot showed that acetylation standing. Dysfunction of histone modification patterns involved of H3K27 was significantly increased in CRC samples com- in the activation of oncogenes and silence tumor suppressor pared with normal tissue [42]. Ashktorab et al. reported that genes have been verified correlated with the etiology of a variety acetylation of H3K12ac and H3K18ac was significantly in- of human diseases including allergic diseases, multiple sclerosis creased in moderate to well differentiated colonic cancer, as well as gastrointestinal cancer [36–38]. Moreover, the alter- whereas decreased in poorly differentiated colonic cancer. ation of histone modification patterns led to the deregulation of They also observed that high level of HDAC2 in adenocarci- gene expression which plays pivotal roles in the formation of noma compared with those in adenoma, suggesting that the colorectal cancer (Table 2). Therefore, It’s important to investi- expression of HDAC2 is closely related to the progression gate the mechanism and biological function of histone modifi- from adenoma to adenocarcinoma [45]. Fraga et al. demon- cation in CRC, thereby improving the clinical diagnosis and strated that colorectal cancer is accompanied by reduced his- therapy of colorectal cancer. tone acetylation on H4K16 in CRC cell lines used both LC- Table 2 Histone acetylation/ Modification and sites Method Impaired function References methylation/phosphory marks in CRC Histone acetylation marks Global H3ac CHIP, WB Hyperacetylation (CRC tissues) [39] Global H4ac IHC Hypoacetylayion (CRC cell lines) induced by CPERT [40] H3K9ac IHC Hypoacetylation (CRC liver metastasis) [41] H3K18ac IHC Hypoactylation (CRC cell lines) [42] H3K27ac MS,WB Hyperacetylation (CRC tissues) [43] H3K56ac WB, CHIP Hypoacetylation (CRC cell lines) through RAS-PI3K [44] signal pathway. RT-qPCR H4K12ac IHC Hypoacetylation (CRC cell lines) [42] H4K16ac LC-ES/MS Hypoacetylation (CRC cell lines, CRC primary tumors) [45, 46] IHC Histone methylation marks H3K4me2 CHIP, WB Hypermethylation (CRC tissues) [39] H3K4me3 IHC Hypomethylation (CRC tissues) [46] H3K9me2 IHC, WB Hypermethylation (CRC cells line, CRC liver [41, 47] metastasis) H3K27me2 IHC Hypermethylation (CRC tissues) [48] H3K27me3 IHC Hypermethylation (CRC tissues) [49] H3K36me2 IHC Hypomethylation (CRC liver metastasis) [48] H3K79me2 IHC Hypermethylation (Patient with CRC) [50] H4K20me2 LC-ES/MS Hypomethylation (CRC cell lines) [45] H4K20me3 CHIP, PCR Hypomethylation (CRC patient’s plasma) [51] Histone phosphorylation marks H3S10ph IHC Hypophosphorylation (CRC cell lines) [52] H2AX IHC Hyperphosphorylation (CRC patients) [53] Histone Modifications and their Role in Colorectal Cancer (Review) 2027 ES-MS and western blot [54]. furthermore, several reports has dimethylated lysine 9 on histone H3 (H3K9me2) in the nuclei indicated that global histone acetylation was positively corre- of adenocarcinoma more than that in adenoma, suggesting lated with tumor stage, lymph metastasis, poor survival, poor that hyperacetylation of H3K9m2 might be relevant to the prognosis, histological subtype and cancer recurrence [17, adenoma transition to adenocarcinoma [63]. Yokoyama et al. 39]. Hashimoto et al. uesd multivariate analysis found that reported that the methylation level of trimethylated lysine 9 on up-regulated global expression level of acetylated histone histone 3 (H3K9me3) was especially up-regulated in invasive H3 (H3Ac) in colorectal cancer tissues was linked to poor regions of colorectal cancer tissues and H3K9 trimethylation overall survival. in addition, high AS (Allred scoring system) was positively related to lymph node metastasis. in addition, score of H3Ac predicted poor prognosis [41]. Tanagawa et al. elevated expression of H3K9 methyltransferase SUV39H1 demonstrated that global hypoacetylation of H3K9 was sig- was facilitated the development of CRC which resulted in a nificantly associated with the histological type of colorectal poor survival rate in mouse [51]. while Gezer.et al. uncovered cancer using immunohistochemistry [46]. Benard et al. found that histone methylation marks H3K9me3 and H4K20me3 that increased nuclear expression of H3K56ac and H4K16ac was significantly decreased in plasma of the patient with was highly correlations with better survival of CRC patients CRC [48]. High AS score of H3K4me2 is dramatically asso- and a lower chance of tumor recurrence [55]. ciated with colorectal cancer clinicopathological factors in- Recent intensively investigations in several of cancers fo- cluding deeper tumor invasion and advanced pathological cus on altering expression of HATs or HDACs uncovered that stage [41]. What is more, Multivariate survival analysis re- they contribute to tumorigenesis. Research data have indicated vealed that the low expression of H3K4me2 could be served that low expression of males absent on the first (MOF) ap- as an independent prognostic factor in CRC patients with peared in colorectal cancer and it mainly correlated with metachronous liver metastasis [46]. The low expression level lymph node metastasis and tumor stage in patients with of H4K20me2 was a common hallmark in CRC cell lines [54]. CRC [56, 57]. Previous studies indicated that CLASS I Tamagawa et al. showed that decrease methylation of HDACs are generally up-regulated in normal colon tissues H3K27me2 in liver metastasis in comparison with primary and colon cancer cell lines [58, 59]. HDAC1 was shown to tumors, whereas the expression of H3K36me2 was reversed. higher in CRC tissues than in normal tissues and low expres- They also demonstrated that the expression level of sion of it indicated better overall survival (OS) [60]. HDAC2 H3K37me2 is positively associated with tumor size and has been found up-regulated in CRC cell lines as compared poorer survival rates and it could be served as an independent with their corresponding normal colonic epithelial cells [61]. prognostic factor for CRC patients with metachronous liver Nemati et al. used RT-PCR observed that an increased level of metastasis [49]. Benard et al. found that an up-regulated level HDAC3 in CRC specimens in relation to poor tumor differ- of H3K27me3 compared to normal counterparts that were detected by immunohistochemically stained (IHC). it closely entiation [62]. In addition, there is also some study indicated that certain histone acetylation can be targeted via specific linked to better patient survival and longer recurrence-free signaling pathway [44]. For example, Liu et al. discovered periods [64]. They also observed that increase expression of that RAS-PI3K signaling down-regulates the level of H3K4me3 and decrease expression of H3K9me3 and H3K56ac which is related to transcription, proliferation, and H4K20me3 were associated with shorter survival and higher migration of cancer cells [40]. The study by Zhang et al. un- chances of tumor recurrence in the early stage of colon cancer covered that cell-cycle related and expression-elevated protein [50]. Additionally, high levels expression of H3K79me2 was (CREPT) cooperated with acetyltransferase P300 stimulates suggested to be a predictor of poor CRC patient survival [65]. the Wnt/−catenin signaling to promote the expression of Global histone methylation is controlled by histone meth- H4Ac and H3K27ac [47]. yltransferase (HMTS) and demethyltransferase (HDMTS) plays an essential role in the regulation of chromatin structure Histone Methylation and Colorectal Cancer and function. Many recent studies have discovered that the alteration of HATs and HDMTs was documented in different Histone methylation is involved in diverse biological func- types of cancers [66]. Kornbluht described that reduction of tions including the formation of heterochromatin, inactivation histone methyltransferase SEDT2 facilitated the CRC devel- of the X chromosome, DNA damage response and transcrip- opment by affecting alternative splicing [67]. The study by tional regulation. The abnormal biological function of histone Qin et al. showed that the expression of G9Awas dramatically methylation regulates pathogenesis of various diseases includ- increased in CRC tumor tissues and overexpression of G9A ing tumors. To date, ectopic expression of histone methylation was mainly correlated with American Joint Committee on and demethylases have been widely described in several can- Cancer staging (AJCC), tumor differentiation and tumor re- cers including colorectal cancer. For instance, Nakazawa et al. lapse of CRC [68]. The histone H3K27 methyltransferase Used both immunohistochemistry and western blot analysis EZH2 expression was up-regulated in CRC, which was pre- dicted shorter survival and advanced stage implying that it have revealed that increased expression of global level of 2028 J. Qin et al. could use to an indicator of clinical outcome in CRC patients Histone Methyltransferase Inhibitors and Treatment [69, 70]. Low nuclear expression of demethylase JMJD3 was of Colorectal Cancer shown in normal colorectal tissues as compared with CRC tissues and low expression of JMJD3 could serve as an inde- Previous studies have emphasized the significance of histone pendent predictor of poor prognosis in patients with CRC methylation in the regulation of gene and other physiological [71]. Elevate expression of Lysine-specific demethylase processes. Furthermore, aberrant histone methylation as a re- (LSD1) observed in colon cancer tissues, and high expression sult of gene mutation is frequently associated with the occur- level of LSD1 was strongly correlated with advanced TNM rence and development of cancer. In order to provide a broader stages and distant metastasis [72]. platform for cancer treatment, the study communities further identify small molecule inhibitors targeting either histone methyltransferases or demethylases for the therapy of CRC, Histone Phosphorylation and Colorectal Cancer therefore most of the histone modifying enzymes serve as a drug target has been widely reported [76]. The study by Hsu Histone phosphorylation is essential for maintaining the equi- et al. was reported that LSD1 inhibitors CBB1003 suppress librium of kinase-phosphatase at kinetochore to refrain from CRC cell growth through down-regulating LGR5 levels and chromosomal instability and cancer. Accordingly, there is an inactivates the Wnt/β-catenin pathway [77]. Enhancer of zeste increasing body of investigation evaluating the impact of dys- homolog 2 (EZH2) is a subunit of the polycomb repressive regulated phosphorylation on the development of many hu- complex 2 (PCR2) and high level of EZH2 has been observed man diseases, including colon cancer [73]. As yet, there are in different cancers including bladder cancer, non-small-cell few researches address the relationship between histone phos- lung cancer as well as colorectal cancer [78]. Therefore, phorylation and colorectal cancer. Several studies have shown EZH2-specific inhibitors have been regarded as an appealing that aberrant of phosphorylation histone has been verified to target as a result of its oncogenic activities. EZH2 inhibitor correlated with the pathogenesis of colorectal cancer. For ex- GSK346 enjoys good anti-tumor efficacy for it can suppress ample, downregulation of dual specificity phosphatase 22 migration, invasion, and proliferation of CRC cells [79]. (DUSP22) expression was observed in colorectal cancer spec- Likewise, in vitro investigations have shown that UCN1999 imens and reduced DUSP22 expression in stage IV patients and GSK 343 are two S-adenosyl-L-methionine (SAM) - was mainly exhibited poor survival outcome [53]. Lee et al. competitive inhibitors which promoted autophagy through revealed that phosphorylation of the H2AX histone (p-H2AX) upregulated the expression of LC3 gene resulted in colorectal have been found elevated in CRC tissues and have been cancer cell death [80]. Verticillin A, a selective histone meth- corrected with a more aggressive type of tumor behavior, as yltransferase inhibitor, not only effectively inhibited the met- well as poor CRC patient survival [74]. Chen et al. found that astatic CRC cell growth but also enhanced the efficacy of CTL PKCƐ modulated MllP-S303 phosphorylation and its expres- immunotherapy to block the progression and metastasis of sion level was associated with metastasis and prognosis of CRC [81]. Nowadays, in vitro study shows that JIB-04, a colorectal cancer [52]. Xiao et al. identified that a reduced novel histone demethylase inhibitors targets colorectal cancer level of Histone H3 at Ser10 (H3S10) was observed in colon stem cells (CSC), was able to repress CSC growth, invasion, cancer. Meanwhile, the phosphorylation of T-LAK cell-origi- and migration to fight against colorectal cancer [82]. nated protein kinase (TOPK) at Y74 and Y272 facilitated the carcinogenesis of colon cancer [75]. Histone Deacetylase Inhibitors and the Treatment of Colorectal Cancer Application of Histone Modification According to HDACis’s molecular function, they can be di- in Colorectal Cancer vided into four major groups: the first group is short-chain fatty acids mainly including phenylbutyrate (PB), valproic Conventional CRC therapies generally including chemother- acid (VPA) and carboxylic acids NaB. The second group is apy, surgery and radiation therapy. However, clinic efficacy of hydroxamates consisting of TSA and SAHA. The third group those treatments is limited. Recent investigation has revealed is benzamides containing MS-275 and MGCD-0103. the that the process of histone modification is reversible and their fourth group is cyclic peptides. As an emerging sort of anti- aberrations can be restored to nearly normal status through cancer drug, increasing evidence has demonstrated that epigenetic therapy. Thus, histone modification serves as a HDACis exert their anti-tumor effects is conveyed by regulat- promising therapeutic target in treating various cancers in ing multiple approaches including induce tumor cells cycle combination with conventional treatment. Histone arrest, inhibit tumor cell growth, differentiation apoptosis. deacetylation and methylation inhibitors are the most widely Furthermore, they facilitate the acetylation of histone and non- applied to colorectal cancer. histone protein resulted in the alteration of their transcriptional Histone Modifications and their Role in Colorectal Cancer (Review) 2029 activity [83]. they inhibit angiogenesis and modulate the benzamides, in various CRC lines and xenograft models it has miRNA expression in tumor progression [84]. Major clinic been shown potent anti-proliferative effects and reduce tumor HDACis for the treatment of CRC is summarized in Table 2. volume [95] and it facilitates Natural killer (NK) cell killing of The current investigation indicated that deregulation of tumor cells by regulation both the NKG2D receptor and its HATs and histone HDACs is engaged in the progression of a ligand, implying that augment NK cell immunotherapy may range of cancers, making them spur the considerable interest of be a potential approach for solid tumors [96]. Furthermore, It is the research community [22, 85]. Thus, HDACis become recently shown that Dihydroxybenzoic acid (DHBA), a kind of appealed target in attempts to attenuate many human cancers benzoic acid derivatives, can suppress HDAC activity resulted including colorectal cancer. Therefore, various histone in cancer cell growth inhibition via the induction of ROS and deacetylase inhibitors (HDIs) become the favored target in at- cellular apoptosis regulated by Caspase-3 [97]. In CRC cell tempts to attenuate much human cancer including colorectal lines, Belinostat induces apoptosis and inhibit colon cancer cell cancer. So far, there are four HDACis have been approved by proliferation by the regulation of proteins including p53, AP1 Food and Drug Administration (FAD) for the treatment of pa- [98]. In HCC and CRC cell lines treated with panobinostat tients with cutaneous T cell lymphoma and peripheral T cell (LBH589) was able to reduce proliferation and vascularization lymphoma [86, 87]. Even if there is a growing list of HDACis lead to a suppressed tumor growth [99], this observation is in applied to colorectal cancer, a wealth of candidates are ongoing accordance with previously published results [100](Table 3). intensively study and clinical trials. For example, Trichostatin It has been noted HDAC inhibitors as monotherapy were A (TSA) suppress the growth of CRC cells in vivo by inducing initially incorporated into the clinical exhibits limited effec- cell cycle arrest and apoptosis through the modulation of tiveness, acquisition of drug resistance as well as adverse ef- JAK2/STAT3 signaling [88]. SAHA known as suberoylanilide fect in the treatment of cancer [101, 102]. Hence, the tendency hydroxamic acid inhibits colon tumor growth via decreasing to apply them in corporation with different types of anti- the expression of histone deacetylases, cyclin D1 and survivin cancer drugs is increasing. Several studies show the combined [89]. in addition, SAHA exerts their anti-proliferative effects in therapies may amplify the anti-tumor effect to suppress refrac- CRC cells through reducing expression of oncogenic miR17– tory tumors [103]. The plethora of investigation involved in 92 cluster miRNAs [90]. Treating colorectal cancer with anti-tumor agents and HDAC inhibitors synergistically used. Valproate (VPA) could depress tumor growth with cell cycle For example, A452, an HDAC6-selective inhibitor, in combi- through alteration of H3 and H4 acetylation [91]. Romidepsin, nation with SAHA enhanced anti-proliferation effects on CRC one of the new class of histone deacetylase inhibitors, exhibits cell lines compared with single-agent therapy [104]. EZH2 its anti-neoplastic effect in colorectal cancer cell lines via in- inhibitors and EGFR inhibitors synergisticll induced autoph- duced alteration in protein modification including acetylation agy and apoptosis, resulting in the inhibition of colon cancer and phosphorylation [92]. In vitro data indicated that it was cells [105]. Combination treatment with vorinostat and able to induce apoptosis by the generation of reactive oxygen bortezomib has better suppress proliferation and induce species (ROS) [93]. Butyrate is a kind of short fatty acid which CRC cell cycle arrest than treatment with single-agent therapy has been shown to significantly effective against the migration [106]. The combined use of Butyrate and irinotecan exhibit and invasion of CRC cell lines via activating the A kt1 and potentiate the antineoplastic effects in CRC cell lines, ERK1/2 signaling [94]. Entinostat (MS-275) is a member of resulting in tumor cell death [107]. while combining entinostat Table 3 The implication of histone acetylase inhibitors(HDACis) in CRC treatment Class Specificity HDACis Experiment design Effect Reference Hydroxamic acids Class I, II Trichostatin A (TSA) CRC cell lines Inhibit CRC cells growth [87] Vorinostat (SAHA) Mouse model Inhibit the growth of colon tumors [88] in nude mice CRC cell lines Anti-proliferative in CRC cell lines [89] Panobistat CRC cell lines HCC cell lines Anti-angiogenic Reduce proliferation [98] Belinostat CRC cell lines Induce CRC cell apoptosis [97] Short-chain fatty acids Class I Butyrate CRC cell lines Inhibit CRC cell migration and invasion [93] Valproic acid (VPA) CRC cell lines Inhibit the growth of CRC cell lines [90] with cell cycle arrest Benzamides Class I Entinostat (MS-275) CRC cell lines mouse model Anti-proliferative effects [94] Benzoic acid Dihydroxy benzoic acid Colon cell lines Induce cancer cell death [96] Cyclic peptides Class I, II Romidepsin (FK228) CRC cell lines Anti-tumor activity [91] 2030 J. Qin et al. with demethylating agent 5-azacitidine applied with metasta- References tic CRC patients have no activity in colorectal cancer [108]. 1. Okugawa Y, Grady WM, Goel A (2015) Epigenetic alterations in Moreover, a variety of HDAC inhibitors are lack of specific- colorectal cancer: emerging biomarkers. Gastroenterology 149(5): ity, thus, it is more critical to devote to developing effective 1204–1225.e12 and specific epigenetic targets against colorectal cancer and 2. Gieni RS, Hendzel MJ (2009) Polycomb group protein gene si- provide an optimized therapeutic regimen for CRC patients. lencing, non-coding RNA, stem cells, and cancer. Biochem Cell Biol 87(5):711–746 Accordingly, in future, the current study is primarily concen- 3. Lawrence M, Daujat S, Schneider R (2016) Lateral thinking: how trates on synergistic effects achieved by the combination use histone modifications regulate gene expression. 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Histone Modifications and their Role in Colorectal Cancer (Review)

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Abstract

The development of colorectal cancer is a complex and multistep process mediated by a variety of factors including the dysregulation of genetic and epigenetic under the influence of microenvironment. It is evident that epigenetics that affects gene activity and expression has been recognized as a critical role in the carcinogenesis. Aside from DNA methylation, miRNA level, and genomic imprinting, histone modification is increasingly recognized as an essential mechanism underlying the occurrence and development of colorectal cancer. Aberrant regulation of histone modification like acetylation, methylation and phosphor- ylation levels on specific residues is implicated in a wide spectrum of cancers, including colorectal cancer. In addition, as this process is reversible and accompanied by a plethora of deregulated enzymes, inhibiting those histone-modifying enzymes activity and regulating its level has been thought of as a potential path for tumor therapy. This review provides insight into the basic information of histone modification and its application in the colorectal cancer treatment, thereby offering new potential targets for treatment of colorectal cancer. . . . . Keywords Histone modification Colorectal cancer Histone acetylation Histone methylation Histone phosphorylation Introduction regulatory mechanisms of epigenetics, which is detected pri- marily in the amino- and carboxy-terminal histone tails. It is The accumulation of genetic and epigenetic dysregulation are also an important mechanism in cancer progression [4]. In this two kinds of separate mechanisms which resulted in tumori- setting, a variety of cancer such as gastric cancer, prostate genesis. Genetic variations have traditionally been regarded as cancer, lung cancer, et al. have been extensively reported to an important player in the occurrence and development of the be correlated with this change [5–7]. Colorectal cancer (CRC) tumor. Nevertheless, current data have been accumulating is a multi-factorial disease and retains its status as the most concerning the epigenetic change which is responsible for common cause of cancer-related death, with more than the genesis and progression of cancer [1]. epigenetics is de- 6000,000 estimated death across the globe every year [8]. fined as the study of changes in the expression and regulation The etiology of colorectal cancer is not completely of genes does not involved in changes in the DNA sequence established, accordingly, it is critical to probe into the molec- which can be classified into DNA methylation, histone mod- ular bases of colorectal cancer and markers for the early diag- ification, miRNA, genomic imprinting and chromosome re- nosis and treatment of this cancer. Aberration in histone mod- modeling [2, 3]. Up to now, DNA methylation and histone ification may become an early diagnosis of colorectal cancer. modification are the most intensively studied epigenetics; This review focus on understanding the role of histone mod- Moreover, Histone modification is one of the important ifications in the progression of colorectal cancer and their application in colorectal cancer may provide a new direction for diagnosis, treatment,and prognosis of colorectal cancer. * Bin Wen wenbin@gzucm.edu.cn Histone Modification Institute of Spleen and Stomach, Guangzhou University of Chinese Medicine, Guangzhou 510000, China Chromatin is a dynamic molecule with multiple structures and there are two basic forms: heterochromatin and euchromatin. Lianyungang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China Epigenetic events are essential to regulate the condensation 2024 J. Qin et al. state of chromatin and hence to regulate the function of ge- modifications of histone lie in inappropriate targeting of nome by means of histone modifications, chromatin remodel- histone-modifying enzymes, including HATs, HDACs, ing, DNA methylation and no-coding RNA [9] Fig. 1. the HMTs, and HDMTS, locally at gene promoters, resulting in fundamental unit of chromatin is nucleosome, which is com- perturbations or mutations in genes [17]. posed of two copies of histones H2A, H2B, H3, and H4, wrapping with approximately 147 base pairs of DNA [10]. Histone Acetylation Histone, one of the major components of chromatin, has long tails protruding away from the nucleosome, which is suscep- Reversible histone acetylation is a dynamic process that is tible to covalently modified at several places [11]. It includes achieved by the addition or removal of histone acetyltransfer- many kinds of covalent modifications, such as acetylation, ases (HATs) and deacetylases (HDACs) [18]. In recent years, phosphorylation, methylation, ubiquitylation, sumoylation the HATs that has been identified mainly includes P300/CBP, and so on [12]. At present, more efforts have been put into GNAT, MYST, P160, PCAF, TAFII230 families [19]. In the two aspects of histone modification namely, acetylation, meth- higher eukaryotes, HDACs can be classified into four groups ylation in terms of the orchestration chromatin structure and on the basis of their homology with the original yeast enzyme gene expression [13, 14]. The combination of single or multi- sequence. Class I HDACs, including HDAC1, 2, 3, 8; Class II histone modification can interact with each other which forms HDACs composed of HDAC4, 5, 6, 7, 9, 10; Class III Bhistone modification code^ [15]. Covalent modification of HDACs, also known as Sirtuins, comprised of SIRT1–7; histones can change the nucleosomal conformation in such a Class IV HDACs, including HDAC11 [20]. Among these way that modulate the chromatin structure and expression of HDACs Class I, II and IV are zinc-dependent, while Class genes [16]. currently, an emerging role of aberrant histone III are NAD -dependent. HATs transfer the acetyl group of modifications have been found in a wide spectrum of cancer, acetyl coenzyme A to the terminal of histone amino acid and giving rise to the role of histone modification is under exten- relax the structure of chromatin under the action of electric sively investigation [13]. The reason why these aberrant charge, which is helpful to transcription by means of Fig. 1 Epigenetics regulate the gene expression without alteration in the setting of colorectal cancer such as acetylation, methylation, and DNA sequence. It mainly consists of DNA methylation, histone phosphorylation. This process is mediated by HATs, HDACs, HMTs, modification, non-coding RNA, chromatin remodeling. a The HDMs and protein kinases (PKs). In open chromatin state, histone tail protruding of amino tails of histone modification can undergo several recruits HATs, HMTs, and PKs which can promote gene transcription. In post-translational modifications that affect the expression of genes. closed chromatin state, histone tail removes these histone-modifying Illustrated is the major histone modifications that have been studied in enzymes which can inhibit the gene transcription. (b) Histone Modifications and their Role in Colorectal Cancer (Review) 2025 increasing the accessibility of DNA. On the contrary, HDAC H3K79 [25]. In addition to the histone methyltransferase, removes the terminal acetyl group of histone lysine making the finding of HDMTs by Shi et al., making the process of the structure of chromatin is compact which result in the inhi- histone methylation more dynamic [26]. From then on, a va- bition of transcription [21]. In generally, hyperacetylation riety of HDMTs has been observed, such as LSD1, UTX, leads to the increased expression of the gene which is related JMJD3, JMJD1A. In contrast to histone acetylation that pro- to the activation of gene transcription, while hypoacetylation motes gene expression, histone lysine methylation has a more means repression of gene expression [22]. complicated effect on gene expression which is depending on the location of modified residues being methylated lead to either transcriptionally-active or -repressive. For instance, Histone Methylation methylation at H3K4 and H3K36 sites activate gene transcrip- tion. Conversely, methylation at H3K9, H3K27, H3K79, Histone methylation refers to the transfer of methyl group to H4K20 sites inhibits gene transcription [27]. the residues of histone arginine or lysine by taking S- adenosylmethionine as methyl donor under the action of his- tone methyltransferases (HMTs). Similar to histone acetyla- Histone Phosphorylation tion, histone methylation is also a dynamic event which is regulated by different types of HMTs and histone Histone phosphorylation, taking place mainly at serines (S), demethytransferases (HDMTs). Histone methylation predom- threonines (T) and tyrosine (Y) residues of histone tails, is one inantly occurs in arginine and lysine residues of histone tails of the histone modifications. Phosphorylation disrupts the in- and is catalyzed by HMTs. Lysine can be monomethylated, teraction between histones and DNA attributed to the instabil- dimethylated or trimethylated, respectively, arginine is either ity of chromatin structure which is requirement for the struc- monomethylated or dimethylated. Furthermore, Lysine meth- tural recombination of chromatin agglutination into homolo- ylation is a more stable and complex modification of gene gous chromosomes during mitosis. It matters that different expression regulation, which occurs mainly on histone H3 types of the phosphorylated site within histone is intimately and H4. There are six sites of lysine methylation that have linked to different chromatin functions. Moreover, Histone been extensively studied such as H3K9, H3K27, H3K36, phosphorylation together with other modifications such as H3K79, and H4K20 [23](Table 1). Protein arginine methyl- histone acetylation is involved in gene transcription, DNA ation is chiefly catalyzed by some members of the protein repair, apoptosis and chromosome condensation. For instance, arginine methyltransferase family including PRMT1, ChIP sequencing data manifested that histone H3 phosphory- PRMT3, PRMT1/HMTA, PRMT4/CARMA, PRMT5 [24]. lated at tyrosine 41 (H3Y41) presents in transcriptional start HMTs comprised of histone arginine methyltransferase sites (TSS) function together with H3K4me3 which implicat- (PRMTs) and histone lysine methyltransferase (HKMTs). ed in transcriptional activation [28]. Furthermore, the combi- PRMTs can be classified as two types: Type I catalyzes the nation of H3Y41 and H3K56 function together can signifi- formation of mono-methylarginine and asymmetric di- cantly increase the accessibility of DNA by more than an order methylarginine; Type II catalyzes the formation of of magnitude [29]. Histone H3 phosphorylated at threo- monomethyl arginine and symmetric di-methylarginine. nines45 (H3T45) takes part in apoptosis and DNA replication HKMTs mainly include Suv39h1, Suv39h2, G9a, EZH2, and can promote the acetylation of H3K56 [30, 31]. There is SET1, SET2, SET9 which contains the SET domain. various kinase responsible for phosphorylation such as Aurora DOT1L is the only lysine methyltransferase without the SET kinase(AKs), protein kinase B (PKB/Akt), cyclin-dependent domain, which can specifically catalyze the methylation of kinases (CDKs), protein kinase C (PKC), casein kinase 2 Table 1 Classification of histone Class Members methyltransferases and demethyltransferases HMTs PRMTs Type I PRM1, PRM3, PMT1/HMT, PRMT4/CAMR1 Type II PRMT5 HKMTs Type I G9a, EZH2, Suv39h1, Suv39h2, SET1, SET2, KMT2A Type II DOTL1 HDMs LSD1, UTX, JMJD3, JMJD1A Adapted from Ref. [23] PRMTs type I: mono-methylarginine and asymmetric dimethylargine; PRMTs type II: mono-methylarginine and symmeric dimethylarginine; HKMTs type I: lysine-specific SET histone transferases; HMTs type II: without lysine SET histone transferases 2026 J. Qin et al. (Ck2) and Rad3 related kinase ATR [32], and so on. H3Y41 is Histone Acetylation and Colorectal Cancer catalyzedbyJAK2 tyrosinekinase(JAK2) [33]. Bub1 is the kinase responsible for phosphorylation of H2AT120 and Up to now, it has been the overwhelming accumulation of H3T3 phosphorylated by Haspin kinase [34, 35]. evidence indicated that histone acetylation finely regulates a wide range of cell functions, such as cell differentiation, as- sembly of the nucleosome, the change of chromatin structure and stability of gene expression [43]. it’s not surprising that Histone Modification and Colorectal Cancer abnormal regulation of histone acetylation is relevance to the predisposition to developing colorectal cancer and this pro- Given that previous research on histone modification in the de- cess is modulated by a plethora of deregulated enzymes in- velopment of colorectal cancer, the relationship between histone cluding HATs, HDATs. Karczmarski et al. used both mass modification and colorectal cancer have been evolving under- spectrometry (MS) and western blot showed that acetylation standing. Dysfunction of histone modification patterns involved of H3K27 was significantly increased in CRC samples com- in the activation of oncogenes and silence tumor suppressor pared with normal tissue [42]. Ashktorab et al. reported that genes have been verified correlated with the etiology of a variety acetylation of H3K12ac and H3K18ac was significantly in- of human diseases including allergic diseases, multiple sclerosis creased in moderate to well differentiated colonic cancer, as well as gastrointestinal cancer [36–38]. Moreover, the alter- whereas decreased in poorly differentiated colonic cancer. ation of histone modification patterns led to the deregulation of They also observed that high level of HDAC2 in adenocarci- gene expression which plays pivotal roles in the formation of noma compared with those in adenoma, suggesting that the colorectal cancer (Table 2). Therefore, It’s important to investi- expression of HDAC2 is closely related to the progression gate the mechanism and biological function of histone modifi- from adenoma to adenocarcinoma [45]. Fraga et al. demon- cation in CRC, thereby improving the clinical diagnosis and strated that colorectal cancer is accompanied by reduced his- therapy of colorectal cancer. tone acetylation on H4K16 in CRC cell lines used both LC- Table 2 Histone acetylation/ Modification and sites Method Impaired function References methylation/phosphory marks in CRC Histone acetylation marks Global H3ac CHIP, WB Hyperacetylation (CRC tissues) [39] Global H4ac IHC Hypoacetylayion (CRC cell lines) induced by CPERT [40] H3K9ac IHC Hypoacetylation (CRC liver metastasis) [41] H3K18ac IHC Hypoactylation (CRC cell lines) [42] H3K27ac MS,WB Hyperacetylation (CRC tissues) [43] H3K56ac WB, CHIP Hypoacetylation (CRC cell lines) through RAS-PI3K [44] signal pathway. RT-qPCR H4K12ac IHC Hypoacetylation (CRC cell lines) [42] H4K16ac LC-ES/MS Hypoacetylation (CRC cell lines, CRC primary tumors) [45, 46] IHC Histone methylation marks H3K4me2 CHIP, WB Hypermethylation (CRC tissues) [39] H3K4me3 IHC Hypomethylation (CRC tissues) [46] H3K9me2 IHC, WB Hypermethylation (CRC cells line, CRC liver [41, 47] metastasis) H3K27me2 IHC Hypermethylation (CRC tissues) [48] H3K27me3 IHC Hypermethylation (CRC tissues) [49] H3K36me2 IHC Hypomethylation (CRC liver metastasis) [48] H3K79me2 IHC Hypermethylation (Patient with CRC) [50] H4K20me2 LC-ES/MS Hypomethylation (CRC cell lines) [45] H4K20me3 CHIP, PCR Hypomethylation (CRC patient’s plasma) [51] Histone phosphorylation marks H3S10ph IHC Hypophosphorylation (CRC cell lines) [52] H2AX IHC Hyperphosphorylation (CRC patients) [53] Histone Modifications and their Role in Colorectal Cancer (Review) 2027 ES-MS and western blot [54]. furthermore, several reports has dimethylated lysine 9 on histone H3 (H3K9me2) in the nuclei indicated that global histone acetylation was positively corre- of adenocarcinoma more than that in adenoma, suggesting lated with tumor stage, lymph metastasis, poor survival, poor that hyperacetylation of H3K9m2 might be relevant to the prognosis, histological subtype and cancer recurrence [17, adenoma transition to adenocarcinoma [63]. Yokoyama et al. 39]. Hashimoto et al. uesd multivariate analysis found that reported that the methylation level of trimethylated lysine 9 on up-regulated global expression level of acetylated histone histone 3 (H3K9me3) was especially up-regulated in invasive H3 (H3Ac) in colorectal cancer tissues was linked to poor regions of colorectal cancer tissues and H3K9 trimethylation overall survival. in addition, high AS (Allred scoring system) was positively related to lymph node metastasis. in addition, score of H3Ac predicted poor prognosis [41]. Tanagawa et al. elevated expression of H3K9 methyltransferase SUV39H1 demonstrated that global hypoacetylation of H3K9 was sig- was facilitated the development of CRC which resulted in a nificantly associated with the histological type of colorectal poor survival rate in mouse [51]. while Gezer.et al. uncovered cancer using immunohistochemistry [46]. Benard et al. found that histone methylation marks H3K9me3 and H4K20me3 that increased nuclear expression of H3K56ac and H4K16ac was significantly decreased in plasma of the patient with was highly correlations with better survival of CRC patients CRC [48]. High AS score of H3K4me2 is dramatically asso- and a lower chance of tumor recurrence [55]. ciated with colorectal cancer clinicopathological factors in- Recent intensively investigations in several of cancers fo- cluding deeper tumor invasion and advanced pathological cus on altering expression of HATs or HDACs uncovered that stage [41]. What is more, Multivariate survival analysis re- they contribute to tumorigenesis. Research data have indicated vealed that the low expression of H3K4me2 could be served that low expression of males absent on the first (MOF) ap- as an independent prognostic factor in CRC patients with peared in colorectal cancer and it mainly correlated with metachronous liver metastasis [46]. The low expression level lymph node metastasis and tumor stage in patients with of H4K20me2 was a common hallmark in CRC cell lines [54]. CRC [56, 57]. Previous studies indicated that CLASS I Tamagawa et al. showed that decrease methylation of HDACs are generally up-regulated in normal colon tissues H3K27me2 in liver metastasis in comparison with primary and colon cancer cell lines [58, 59]. HDAC1 was shown to tumors, whereas the expression of H3K36me2 was reversed. higher in CRC tissues than in normal tissues and low expres- They also demonstrated that the expression level of sion of it indicated better overall survival (OS) [60]. HDAC2 H3K37me2 is positively associated with tumor size and has been found up-regulated in CRC cell lines as compared poorer survival rates and it could be served as an independent with their corresponding normal colonic epithelial cells [61]. prognostic factor for CRC patients with metachronous liver Nemati et al. used RT-PCR observed that an increased level of metastasis [49]. Benard et al. found that an up-regulated level HDAC3 in CRC specimens in relation to poor tumor differ- of H3K27me3 compared to normal counterparts that were detected by immunohistochemically stained (IHC). it closely entiation [62]. In addition, there is also some study indicated that certain histone acetylation can be targeted via specific linked to better patient survival and longer recurrence-free signaling pathway [44]. For example, Liu et al. discovered periods [64]. They also observed that increase expression of that RAS-PI3K signaling down-regulates the level of H3K4me3 and decrease expression of H3K9me3 and H3K56ac which is related to transcription, proliferation, and H4K20me3 were associated with shorter survival and higher migration of cancer cells [40]. The study by Zhang et al. un- chances of tumor recurrence in the early stage of colon cancer covered that cell-cycle related and expression-elevated protein [50]. Additionally, high levels expression of H3K79me2 was (CREPT) cooperated with acetyltransferase P300 stimulates suggested to be a predictor of poor CRC patient survival [65]. the Wnt/−catenin signaling to promote the expression of Global histone methylation is controlled by histone meth- H4Ac and H3K27ac [47]. yltransferase (HMTS) and demethyltransferase (HDMTS) plays an essential role in the regulation of chromatin structure Histone Methylation and Colorectal Cancer and function. Many recent studies have discovered that the alteration of HATs and HDMTs was documented in different Histone methylation is involved in diverse biological func- types of cancers [66]. Kornbluht described that reduction of tions including the formation of heterochromatin, inactivation histone methyltransferase SEDT2 facilitated the CRC devel- of the X chromosome, DNA damage response and transcrip- opment by affecting alternative splicing [67]. The study by tional regulation. The abnormal biological function of histone Qin et al. showed that the expression of G9Awas dramatically methylation regulates pathogenesis of various diseases includ- increased in CRC tumor tissues and overexpression of G9A ing tumors. To date, ectopic expression of histone methylation was mainly correlated with American Joint Committee on and demethylases have been widely described in several can- Cancer staging (AJCC), tumor differentiation and tumor re- cers including colorectal cancer. For instance, Nakazawa et al. lapse of CRC [68]. The histone H3K27 methyltransferase Used both immunohistochemistry and western blot analysis EZH2 expression was up-regulated in CRC, which was pre- dicted shorter survival and advanced stage implying that it have revealed that increased expression of global level of 2028 J. Qin et al. could use to an indicator of clinical outcome in CRC patients Histone Methyltransferase Inhibitors and Treatment [69, 70]. Low nuclear expression of demethylase JMJD3 was of Colorectal Cancer shown in normal colorectal tissues as compared with CRC tissues and low expression of JMJD3 could serve as an inde- Previous studies have emphasized the significance of histone pendent predictor of poor prognosis in patients with CRC methylation in the regulation of gene and other physiological [71]. Elevate expression of Lysine-specific demethylase processes. Furthermore, aberrant histone methylation as a re- (LSD1) observed in colon cancer tissues, and high expression sult of gene mutation is frequently associated with the occur- level of LSD1 was strongly correlated with advanced TNM rence and development of cancer. In order to provide a broader stages and distant metastasis [72]. platform for cancer treatment, the study communities further identify small molecule inhibitors targeting either histone methyltransferases or demethylases for the therapy of CRC, Histone Phosphorylation and Colorectal Cancer therefore most of the histone modifying enzymes serve as a drug target has been widely reported [76]. The study by Hsu Histone phosphorylation is essential for maintaining the equi- et al. was reported that LSD1 inhibitors CBB1003 suppress librium of kinase-phosphatase at kinetochore to refrain from CRC cell growth through down-regulating LGR5 levels and chromosomal instability and cancer. Accordingly, there is an inactivates the Wnt/β-catenin pathway [77]. Enhancer of zeste increasing body of investigation evaluating the impact of dys- homolog 2 (EZH2) is a subunit of the polycomb repressive regulated phosphorylation on the development of many hu- complex 2 (PCR2) and high level of EZH2 has been observed man diseases, including colon cancer [73]. As yet, there are in different cancers including bladder cancer, non-small-cell few researches address the relationship between histone phos- lung cancer as well as colorectal cancer [78]. Therefore, phorylation and colorectal cancer. Several studies have shown EZH2-specific inhibitors have been regarded as an appealing that aberrant of phosphorylation histone has been verified to target as a result of its oncogenic activities. EZH2 inhibitor correlated with the pathogenesis of colorectal cancer. For ex- GSK346 enjoys good anti-tumor efficacy for it can suppress ample, downregulation of dual specificity phosphatase 22 migration, invasion, and proliferation of CRC cells [79]. (DUSP22) expression was observed in colorectal cancer spec- Likewise, in vitro investigations have shown that UCN1999 imens and reduced DUSP22 expression in stage IV patients and GSK 343 are two S-adenosyl-L-methionine (SAM) - was mainly exhibited poor survival outcome [53]. Lee et al. competitive inhibitors which promoted autophagy through revealed that phosphorylation of the H2AX histone (p-H2AX) upregulated the expression of LC3 gene resulted in colorectal have been found elevated in CRC tissues and have been cancer cell death [80]. Verticillin A, a selective histone meth- corrected with a more aggressive type of tumor behavior, as yltransferase inhibitor, not only effectively inhibited the met- well as poor CRC patient survival [74]. Chen et al. found that astatic CRC cell growth but also enhanced the efficacy of CTL PKCƐ modulated MllP-S303 phosphorylation and its expres- immunotherapy to block the progression and metastasis of sion level was associated with metastasis and prognosis of CRC [81]. Nowadays, in vitro study shows that JIB-04, a colorectal cancer [52]. Xiao et al. identified that a reduced novel histone demethylase inhibitors targets colorectal cancer level of Histone H3 at Ser10 (H3S10) was observed in colon stem cells (CSC), was able to repress CSC growth, invasion, cancer. Meanwhile, the phosphorylation of T-LAK cell-origi- and migration to fight against colorectal cancer [82]. nated protein kinase (TOPK) at Y74 and Y272 facilitated the carcinogenesis of colon cancer [75]. Histone Deacetylase Inhibitors and the Treatment of Colorectal Cancer Application of Histone Modification According to HDACis’s molecular function, they can be di- in Colorectal Cancer vided into four major groups: the first group is short-chain fatty acids mainly including phenylbutyrate (PB), valproic Conventional CRC therapies generally including chemother- acid (VPA) and carboxylic acids NaB. The second group is apy, surgery and radiation therapy. However, clinic efficacy of hydroxamates consisting of TSA and SAHA. The third group those treatments is limited. Recent investigation has revealed is benzamides containing MS-275 and MGCD-0103. the that the process of histone modification is reversible and their fourth group is cyclic peptides. As an emerging sort of anti- aberrations can be restored to nearly normal status through cancer drug, increasing evidence has demonstrated that epigenetic therapy. Thus, histone modification serves as a HDACis exert their anti-tumor effects is conveyed by regulat- promising therapeutic target in treating various cancers in ing multiple approaches including induce tumor cells cycle combination with conventional treatment. Histone arrest, inhibit tumor cell growth, differentiation apoptosis. deacetylation and methylation inhibitors are the most widely Furthermore, they facilitate the acetylation of histone and non- applied to colorectal cancer. histone protein resulted in the alteration of their transcriptional Histone Modifications and their Role in Colorectal Cancer (Review) 2029 activity [83]. they inhibit angiogenesis and modulate the benzamides, in various CRC lines and xenograft models it has miRNA expression in tumor progression [84]. Major clinic been shown potent anti-proliferative effects and reduce tumor HDACis for the treatment of CRC is summarized in Table 2. volume [95] and it facilitates Natural killer (NK) cell killing of The current investigation indicated that deregulation of tumor cells by regulation both the NKG2D receptor and its HATs and histone HDACs is engaged in the progression of a ligand, implying that augment NK cell immunotherapy may range of cancers, making them spur the considerable interest of be a potential approach for solid tumors [96]. Furthermore, It is the research community [22, 85]. Thus, HDACis become recently shown that Dihydroxybenzoic acid (DHBA), a kind of appealed target in attempts to attenuate many human cancers benzoic acid derivatives, can suppress HDAC activity resulted including colorectal cancer. Therefore, various histone in cancer cell growth inhibition via the induction of ROS and deacetylase inhibitors (HDIs) become the favored target in at- cellular apoptosis regulated by Caspase-3 [97]. In CRC cell tempts to attenuate much human cancer including colorectal lines, Belinostat induces apoptosis and inhibit colon cancer cell cancer. So far, there are four HDACis have been approved by proliferation by the regulation of proteins including p53, AP1 Food and Drug Administration (FAD) for the treatment of pa- [98]. In HCC and CRC cell lines treated with panobinostat tients with cutaneous T cell lymphoma and peripheral T cell (LBH589) was able to reduce proliferation and vascularization lymphoma [86, 87]. Even if there is a growing list of HDACis lead to a suppressed tumor growth [99], this observation is in applied to colorectal cancer, a wealth of candidates are ongoing accordance with previously published results [100](Table 3). intensively study and clinical trials. For example, Trichostatin It has been noted HDAC inhibitors as monotherapy were A (TSA) suppress the growth of CRC cells in vivo by inducing initially incorporated into the clinical exhibits limited effec- cell cycle arrest and apoptosis through the modulation of tiveness, acquisition of drug resistance as well as adverse ef- JAK2/STAT3 signaling [88]. SAHA known as suberoylanilide fect in the treatment of cancer [101, 102]. Hence, the tendency hydroxamic acid inhibits colon tumor growth via decreasing to apply them in corporation with different types of anti- the expression of histone deacetylases, cyclin D1 and survivin cancer drugs is increasing. Several studies show the combined [89]. in addition, SAHA exerts their anti-proliferative effects in therapies may amplify the anti-tumor effect to suppress refrac- CRC cells through reducing expression of oncogenic miR17– tory tumors [103]. The plethora of investigation involved in 92 cluster miRNAs [90]. Treating colorectal cancer with anti-tumor agents and HDAC inhibitors synergistically used. Valproate (VPA) could depress tumor growth with cell cycle For example, A452, an HDAC6-selective inhibitor, in combi- through alteration of H3 and H4 acetylation [91]. Romidepsin, nation with SAHA enhanced anti-proliferation effects on CRC one of the new class of histone deacetylase inhibitors, exhibits cell lines compared with single-agent therapy [104]. EZH2 its anti-neoplastic effect in colorectal cancer cell lines via in- inhibitors and EGFR inhibitors synergisticll induced autoph- duced alteration in protein modification including acetylation agy and apoptosis, resulting in the inhibition of colon cancer and phosphorylation [92]. In vitro data indicated that it was cells [105]. Combination treatment with vorinostat and able to induce apoptosis by the generation of reactive oxygen bortezomib has better suppress proliferation and induce species (ROS) [93]. Butyrate is a kind of short fatty acid which CRC cell cycle arrest than treatment with single-agent therapy has been shown to significantly effective against the migration [106]. The combined use of Butyrate and irinotecan exhibit and invasion of CRC cell lines via activating the A kt1 and potentiate the antineoplastic effects in CRC cell lines, ERK1/2 signaling [94]. Entinostat (MS-275) is a member of resulting in tumor cell death [107]. while combining entinostat Table 3 The implication of histone acetylase inhibitors(HDACis) in CRC treatment Class Specificity HDACis Experiment design Effect Reference Hydroxamic acids Class I, II Trichostatin A (TSA) CRC cell lines Inhibit CRC cells growth [87] Vorinostat (SAHA) Mouse model Inhibit the growth of colon tumors [88] in nude mice CRC cell lines Anti-proliferative in CRC cell lines [89] Panobistat CRC cell lines HCC cell lines Anti-angiogenic Reduce proliferation [98] Belinostat CRC cell lines Induce CRC cell apoptosis [97] Short-chain fatty acids Class I Butyrate CRC cell lines Inhibit CRC cell migration and invasion [93] Valproic acid (VPA) CRC cell lines Inhibit the growth of CRC cell lines [90] with cell cycle arrest Benzamides Class I Entinostat (MS-275) CRC cell lines mouse model Anti-proliferative effects [94] Benzoic acid Dihydroxy benzoic acid Colon cell lines Induce cancer cell death [96] Cyclic peptides Class I, II Romidepsin (FK228) CRC cell lines Anti-tumor activity [91] 2030 J. 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