Review Article
Recent advances of histone modification in gastric cancer ABSTRACT Epigenetics play important roles during development progress of tumor. The histone modifications are the most important constituted field. Recently, accumulating research focused on exploring the roles of those modifications in regulating tumorigenesis. Moreover, the dysregulation of histone modifications is supposed to have vital clinical significance. Numerous histone modifications have the potential to be prognostic biomarkers, monitoring response of therapy, early diagnostic markers. Herein, we review the recent advances of histone modifications involving development of gastric cancer. KEY WORDS: Acetylation, gastric cancer, histone modification, methylation, phosphorylation
INTRODUCTION The occurrence and development of tumor are resulted from genetic and epigenetic dysregulation. [1‑3] Genetic variations, such as gene mutation, translate, transpositions, are always recognized as the principal factor of tumor development. Accumulating evidence demonstrated that the epigenetic changes caused by the microenvironment also played important roles.[4,5] The epigenetic is referred to the changes of heritable gene expression and regulation without sequence rearrangement.[6] At present, DNA methylation, histone modification, genomic imprinting, chromosome remodeling, miRNAs are known as epigenetic changes. Among those events, high methylation of CpG islands in the promoter of tumor suppressor genes is the most common.[7] Moreover, some epigenetic changes are associated with chromosome, of which are core histone proteins modification (namely histone modification). The principal of histone modification is that the N terminus of core proteins (H2A, H2B, H3, H4) are modified with multiple covalent modification after translation, such as acetylation, methylation, and phosphorylation. [8] As the discovery of a large number of histone modification enzymes and the proposed of “histone codon”,[9] histone modification is suggested not only to regulate normal physiological function, such as DNA replication, translation, or repair, but also to involve in tumor development. In view of this, more and more attentions had been focused on histone modification. Numerous studies have explored the changes in multiple kinds of cancer, such as prostatic cancer, lung cancer, renal cancer, C240
breast cancer, ovarian cancer, and pancreatic cancer. [10,11] More importantly, those changes indicated pivotal clinical significance. In addition, a lot of the catalytic enzyme of histone were found to have high activities in tumor.[11] Gastric cancer was ranked as the top morbidity and mortality rates. The investigations on gastric cancer histone modification would promote understanding the mechanism of gastric cancer development. [3] Moreover, those effects would improve diagnosis or therapy of gastric cancer. In this review, we conclude and discuss the recent progress of histone modifications involving development of gastric cancer.
Wen‑Yan Yang, Jing‑Liang Gu, Tian‑Min Zhen Key Laboratory of Medical Library, Shandong Institute of Medicine and Health Information, Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan 250062, China For correspondence: Prof. Tian‑Min Zhen, Shandong Institute of Medicine and Health Information, Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan 250062, China. E‑mail: tmzhen@sina. com
CHROMATIN STRUCTURE Eukaryotic chromosome is complex and constituted with DNA, histone, nonhistone molecules. There are two basic forms, heterochromatin that exist in condensed chromosome with transcription inhibited, and euchromatin that was the loos chromosome with active transcription.[12] The basic units of chromatin are nucleosome, core granules are composed of histone octamer (core histones), which contains two H2A, H2B, H3 and H4, and about 146 bp DNA that intertwined on the core histones. Furthermore, the core histones would interact through H1 to form chromatin. Every core histone contained a spherical domain and an exposed N terminal. After finishing histone translation, the N terminal would be modified with acetylation, methylation, phosphorylation, ubiquitination, sumoylation, adenosine diphosphate (ADP) glycosylation, or carbonylation Fuchs et al. [13] Histone modifications can regulate structures and
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Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
Yang, et al.: Histone modification in gastric cancer
functions of chromosome by two ways. Firstly, histones are enriched with positively charged arginine and lysine, which can tightly bind to DNA with a negative charge. Thus, histone modifications would affect the interaction between DNA and histone. Secondly, histone modification prone to produce binding surface of protein recognized motif. It recruited special protein complex to the binding surface. Thus, histone modification could determine active or inactive of chromosome by changing its structures, as results, to control cellular physical pathways.
promotes the interaction between transcription factors or synergy transcription factors and DNA chains. Thereafter, the histone acetylation activates specific gene transcription. On the contrary, HDAC could remove the acetyls from histone Lys and recover the positive charge, thus the positively charged Lys increase the attraction between negatively charged DNA chain and histone, preventing transcriptional regulatory elements binding to promoters and inhibiting the transcription. In generally, the active region of nucleosomal histone is always under hyper‑acetylation. Therefore, the acetylation is related to gene activation while deacetylation means gene silence.[20,21]
HISTONE MODIFICATION It has been known that there were nine histone modifications, acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP glycosylation, carbonylation, proline isomerization, and propionylation.[13,14] Currently, numerous studies had focused on exploring the roles of acetylation, methylation, and phosphorylation, moreover, acetylation and methylation of H3 or H4 were most commonly.[15,16] These histone modifications can combine with each other. For instance, histone methylation in lysine includes single, double, three methylation.[17] Furthermore, histone modification can regulate and control chromosome structures to affect DNA functions. Thus, histone modification may be fine mechanisms of gene expression orchestra. Histone acetylation Histone acetylation is a reversible process of dynamic balance in healthy physiological process. Histone acetyltransferase (HATs) and histone deacetylase (HDACs) are the most important enzymes to maintain balance between acetylation and deacetylation. According to cellular location and functions, HATs could be divided into two types: Type A in the nucleus, which exhibits function on regulating gene transcription; while, type B in cytoplasm catalyzes acetylation of nonhistone proteins. HATs mainly include GNAT, MYST, MOZ/YBF2/SAS2/ TIP60 and CBP/p300 families. All these three families exist in complexes forms, such as GCN5, PCAG, MORF, CBP/p300. The complexes would interact and effect each other. Thereby, those interactions could play important roles in cell development, differentiation, or cycles. Currently, HDACs are divided into four Class from I–IV; I includes 1, 2, 3, 8; II includes 4–7, 9, 10; III includes SITR1‑7; IV includes HDAC11, which contains some characteristics of I and II.[18] HDACs I mainly regulate histone acetylation and chromosome structures; HDACs II and IV probably catalyze nonhistone deacetylation in the cytoplasm.[19] The members of SIRTs family regulate cell senescence, DNA repair, cell cycles.[11] The histone acetylation is the process that HATs transfer acetyl from acetyl coenzyme A to the specific e‑amino of Lys residual in the amino terminal of core proteins. The positive charge is removed, while DNA molecular with a negative charge is in favor of unfolding the DNA conformation and loosening nucleosome. Furthermore, the loosened structure Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
Histone methylation Histone protein now divides into five classes: H1, H2A, H2B, H3, and H4. Methylation sites are often found in lysine or arginine of H3 or H4. In special, both single and double methylations can be found in arginine while there are one, two, and three methyl in lysine. Histone methyltransferases (HMTs) include histone arginine methyl transferase (HRMTs) and histone lysine methylation transferase (HKMTs). Furthermore, HRMTs comprise two types: Type I catalyzes arginine single methylation and asymmetric double methylation; Type II enzyme catalyzes arginine single or symmetric double methylation.[22] HKMTs are composed with lysine specific SET region HMTs and without lysine SET HMTs.[23,24] Previously, methylation was thought as irreversible progress. After the finding of fist histone demethylase (HDMS), LSD1,[25] the histone methylation were proved to be one of reversible program, just like acetylation. Thereafter, a large amount of HDMS were identified, such as JHDM1A, JMJD2/KDM4.PUT1. However, different from acetylation, the HDMS functions are variant with different sites and types, for example, H3K9 and H4K20 could inhibit gene expression while H3K4, H3K36, and H3K79 could activate gene expression. In addition, the single methylation of H3K27 could active gene expression, while H3K37 double or trimethylation inhibit gene expression. Histone phosphorylation Histone phosphorylation is adding PO4 residual to terminus of histone. This reversible modification often happened in serine, threonine and tyrosine. The histone phosphorylation changes chromosome structures and regulates the interaction with transcription factors to affect gene transcription. As well as, different phosphorylations are related with variously cellular process such as transcription, mitosis, apoptosis, DNA repair. Up to now, the histone H3 phosphorylation has been extensively explored. Moreover, series of conservative phosphorylated regions were identified (such as T3, S10, T11, S28, T45). The serine, threonine and tyrosine of H1, H2A, H2B and H4 were also prone to be phosphorylated. The phosphorylated processes are catalyzed by various kinases. For instance, DNA damage signaling pathways induce histone H2AX to be phosphorylated and which mainly dependent on triphosphate inositol kinase related kinase. [26] Mst1 kinase could catalyze phosphorylation of H2BS14, which play important roles in cell apoptosis.[27] The transcription C241
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activation related phosphorylation of histone H3S10 and H3S28 were catalyzed by Aurora kinase.[28] MSK/RSK/Jil‑1 kinase family could mediate H3S10 phosphorylation to regulate gene expression.[28] Regarding to function, histone phosphorylation mainly regulates gene transcriptions in related signaling pathways. Mahadevan et al.[29] found that the fast phosphorylation of H3 always accompanied with activation of c‑fos and c‑jun in 1991. After that, more and more evidence demonstrated that the phosphorylation of H3 Ser10 played extremely important roles during activating transcription in eukaryotes.[28] Protein kinase A can mediate H3 phosphorylation on serine 10, which is associated with transcriptional activation of ERK‑mitogen‑activated protein kinase (MAPK) signaling pathway and c‑fos. [30] Indirectly immune location assays also proved that ERK‑MAPK pathway could result in multiple sites H3 phosphorylation, among of them, some phosphorylated H3 might associate with quick activations of genes involving in ERK‑MAPK pathway.[31] In addition, H3 Ser10 phosphorylation can initiate cellular mitosis and promote chromatic aggregation at early G2 stage.[32‑34]
regions. It is demonstrated that histone H4 had a significant low acetylation levels in gastric tissue. Moreover, the acetylation was associated with tumor stage, invasion, and lymphatic metastasis.[46] Recently, Kang et al.[47] identified that HDAC4 could facilitate gastric cancer progression by p21 repression. Park et al.[48] showed that the acetylation level of H3K9 in gastric cancer tissues was related with WHO grade and Laruen classification. Meanwhile, H4K16 acetylation was unrelated with any clinical parameters. Mutze et al.[49] discovered that HDAC1 and HDAC2 had high levels in gastric cancer tissues, and HDAC1 could be used as one of the potential risk stratification factors for patients who are sensitivity to chemotherapy.
Histone modification affected the important physical functions. Thus, the dysregulation would cause abnormal gene expressions to change their physiological functions, leading to carcinogenesis.[3,42]
Histone methylation and gastric cancer The researches about histone methylation on gastric cancer mainly focused on H3 and H4.[50] Park et al.[48] discovered that the triple methylation on H3K9 was associated with tumor stage, lymphovascular invasion, recurrence, and overall survival rates. Multivariate survival analysis revealed that the triple methylation of H3K9 was independent prognostic factor of gastric cancer.[48] Zhang et al.[51] analyzed triple methylation between gastric cancerous and matched adjacent normal tissues by chromatin immunoprecipitation linked to the microarray (ChIP‑chip) approach. They proved that there were 128 genes in total with significantly differences in H3K27 triple methylation on CpG islands between cancerous and normal tissues. The work from Gao et al.[52] also provide evidence for these. These might help to illustrate the mechanism of gastric cancer development. Meng et al.[53] identified that low H3K9 acetylation, H3K9 di‑methylation and DNA methylation in the promoter regions of tumor suppressor gene p16 would in combination decrease expression of p16. Moreover, 5‑aza‑2’‑deoxycytidine (5‑Aza‑dC) inhibited H3k9 di‑methylation and DNA methylation, and increased H3K9 acetylation to promote p16 expression. Furthermore, the enzyme that the catalyzed methylation also be changed.[53] Matsukawa et al.[54] demonstrated that EZH2 was over‑expressed in gastric cancer and associated with tumor size, invasion depth, vascular invasion, lymph node metastasis, and clinical stages. Multivariate survival analysis suggested that high levels of EZH2 meant poor prognosis. Fujii and Ochiai.[55] discovered that EZH2 caused H3K27 methylation in the promoter of E‑cadherin, thus down‑regulated its expression. This would be the reason that over‑expression EZH2 related with poor prognosis.
Histone acetylation and gastric cancer A large number of studies about histone acetylation on malignant tumor have been conducted.[43] However, more extensively exploration is still needed on its roles in gastric cancer. Mitani et al.[44] found that tumor suppressor gene P21 WAP1/CIP1 with low levels of H3 acetylation on promoter resulted in its down‑regulation. Xia et al.[45] identified that Helicobacter pylori increased expression of P21 WAP1/CIP1 by maintaining high acetylation levels of H4 on its promoter
Histone phosphorylation and gastric cancer There were fewer reports about histone phosphorylation on gastric cancer. Takahashi et al.[56] revealed that high levels of H3 phosphorylation were found in gastric cancer. Furthermore, they found that H3 phosphorylation was useful for the prediction of prognosis in gastric cancer and was associated with histological types, vascular invasion, and lymphatic metastasis. Fehri et al.[57] proved that H. pylori decreased phosphorylation levels of H3S10 and H3T3 to regulate cell
The relationships among different histone modifications The histone modifications involved gene activation or inhibition are not independent, but interactive, including synergy and antagonism. For example, H3 S10 phosphorylation promotes H3K14 acetylation and H3K4 methylation. Moreover, it would inhibit H3K9 methylation [35,36] and H2BK123 ubiquitination and mediate H3K4 or H3K79 methylation translated activation.[37] However, the H3K9 methylation prevents H3S10 phosphorylation and gene transcription, while, H3K9 acetylation is related with transcription activation.[36] In addition, histone modifications are also related to epigenetic, important pathways. For instance, histone modification and DNA methylation could cooperate to silence some antitumor gene.[38] MiRANs could regulate epigenetic modification by targeting to catalyzing enzyme (enhancer of zeste homolog 2 [EZH2]) and DNA methylase (DNAMT3A, DNMT3B).[39,40] The triple methylation of histone H3K27 was catalyzed by EZH2 and related with Ras, NF‑κB, SATA, Wnt/β‑catenin pathways.[41] HISTONE MODIFICATION AND GASTRIC CANCER
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cycles. This might be one of the novel important mechanisms of H. pylori inducing the development of gastric cancer. THE CLINICAL APPLICATION OF HISTONE MODIFICATION Similar with other epigenetic, the histone modifications were reversible progresses, providing principle evidence for tumor‑targeted therapy. So far, accumulating studies emphasized on histone deacetylation and methylation inhibitors, such as trichostatin A (TSA), SAHA, and DZNep, BIX‑01294.[58‑62] Among them, SAHA had been approved by US Food and Drug Administration to apply in clinical for the treatment of cutaneous T‑cell lymphomas.[62] During carcinogenesis and development, various epigenetic modifications interacted with catalytic enzymes. The designed inhibitors on a series epigenetic modifications showed adverse effects in the treatment of tumors. For instance, DNA methylation inhibitors 5‑aza, 5‑aza‑dC and etc., are insufficient in specificity and stability in vivo, with unsatisfactory clinical benefits. Although HDAC could induce tumor cell cycle arrest, differentiation, or apoptosis. Moreover, some agents, such as TSA, SAA, MS‑275, have been tested in phase I and II clinical trials.[59,63‑67] However, HDAC shows nonsignificantly difference in comparing with DNA methylation inhibitors. Therefore, combined application of multiple inhibitors has become a hot‑topic for the clinical investigations of histone modification inhibitors. It is reported that combined DNMT and HDAC inhibitors could activate expression of tumor repress genes, including MLH1, TIMP3, CDKN2B, CDKN2A, and ARHI, promoting tumor cell apoptosis.[68‑72] Manuyakorn et al.[73] found that the pancreatic cancer patients with low levels di‑methylation of H3K4, H3K9, and acetylation of H3K18 were not benefit from 5‑fluoouracil (5‑FU) chemotherapy. It is supposed that the combination of acetylated and methylated inhibitors might improve histone acetylation and thus improve prognosis of patients with pancreatic cancer. Histone modification could be served as biomarkers for prognosis, therapy response and others.[74] Seligson et al.[75] identified that low levels of histone modification had a poor prognosis in prostatic cancers patients with surgical resection of primary tumor lesions. Moreover, in comparing with other clinical factors, histone modification was the only independent prognostic factor. Some studies revealed that multiple kinds of histone modification could be used as independent prognostic markers for prostatic cancer, lung cancer, renal cancer, pancreatic cancer, or ovarian cancer. Manuyakorn et al.[73] also explored that H3K4 and H3K9 di‑methylation, H3K18 acetylation, could serve as potential biomarkers response to gemcitabine treatment on pancreatic cancer. They proved that pancreatic cancer patients with low acetylation of histone were more favorable to gemcitabine treatment with higher over survival rates in the comparison with 5‑FU. Broeck et al.[76] found that H4K20 methylations were lost in nonsmall cell lung cancer precancerous lesion. Therefore, H4K20 methylation might be used as monitor biomarkers for nonsmall cell lung Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
cancer. Deligezer et al.[77] discovered that H3K9 methylation were found in plasma by chromatin immunoprecipitation. All of those evidences provided the potential that histone modifications could be used as tumor markers in practice. CONCLUSION In a word, histone modifications were part of epigenetic and attracted a lot of attention on its roles in carcinogenesis and tumor development. However, the clinical application of histone modifications was limited in overall levels of modification. Until now, the clinical application value of some specific promoter histone modifications still undefined. In addition, malignant tumor was disease with obviously heterogeneity. Thus, it still need to be extensively explored the roles of histone modification. ACKNOWLEDGEMENTS This project is supported by Science and Technology Department of Shandong Province.
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the histone methyltransferase EZH2, induces apoptosis and reduces cell migration in chondrosarcoma cells. PLoS One 2014;9:e98176. 61. Savickiene J, Treigyte G, Stirblyte I, Valiuliene G, Navakauskiene R. Euchromatic histone methyltransferase 2 inhibitor, BIX‑01294, sensitizes human promyelocytic leukemia HL‑60 and NB4 cells to growth inhibition and differentiation. Leuk Res 2014;38:822‑9. 62. Cortez CC, Jones PA. Chromatin, cancer and drug therapies. Mutat Res 2008;647:44‑51. 63. Gore L, Rothenberg ML, O’Bryant CL, Schultz MK, Sandler AB, Coffin D, et al. A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS‑275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res 2008;14:4517‑25. 64. Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, et al. Phase I and pharmacokinetic study of MS‑275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 2005;23:3912‑22. 65. Xiao W, Chen X, Liu X, Luo L, Ye S, Liu Y. Trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial‑mesenchymal transition in retinal pigment epithelium cells. J Cell Mol Med 2014;18:646‑55. 66. Malle E, De Beer FC. Human serum amyloid A (SAA) protein: A prominent acute‑phase reactant for clinical practice. Eur J Clin Invest 1996;26:427‑35. 67. Rau B, Steinbach G, Baumgart K, Gansauge F, Grünert A, Beger HG. Serum amyloid A versus C‑reactive protein in acute pancreatitis: Clinical value of an alternative acute‑phase reactant. Crit Care Med 2000;28:736‑42. 68. Zhu WG, Lakshmanan RR , Beal MD, Otterson GA. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Res 2001;61:1327‑33. 69. Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR, et al. Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. Hum Mol Genet 2003;12:1791‑800.
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70. Meng CF, Zhu XJ, Peng G, Dai DQ. Re‑expression of methylation‑induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines. World J Gastroenterol 2007;13:6166‑71. 71. Miller JL, Grant PA. The role of DNA methylation and histone modifications in transcriptional regulation in humans. Subcell Biochem 2013;61:289‑317. 72. Meng CF, Zhu XJ, Peng G, Dai DQ. Role of histone modifications and DNA methylation in the regulation of O6‑methylguanine‑DNA methyltransferase gene expression in human stomach cancer cells. Cancer Invest 2010;28:331‑9. 73. Manuyakorn A, Paulus R, Farrell J, Dawson NA, Tze S, Cheung‑Lau G, et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: Results from RTOG 9704. J Clin Oncol 2010;28:1358‑65. 74. Zhang W, Li Y, Yang S, Li W, Ming Z, Zhang Y, et al. Differential mitochondrial proteome analysis of human lung adenocarcinoma and normal bronchial epithelium cell lines using quantitative mass spectrometry. Thorac Cancer 2013;4:373‑9. 75. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 2005;435:1262‑6. 76. Van Den Broeck A, Brambilla E, Moro‑Sibilot D, Lantuejoul S, Brambilla C, Eymin B, et al. Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non‑small cell lung cancer. Clin Cancer Res 2008;14:7237‑45. 77. Deligezer U, Akisik EE, Erten N, Dalay N. Sequence‑specific histone methylation is detectable on circulating nucleosomes in plasma. Clin Chem 2008;54:1125‑31. Cite this article as: Yang WY, Gu JL, Zhen TM. Recent advances of histone modification in gastric cancer. J Can Res Ther 2014;10:240-5. Source of Support: Nil, Conflict of Interest: None declared.
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Recent advances of histone modification in gastric cancer ABSTRACT Epigenetics play important roles during development progress of tumor. The histone modifications are the most important constituted field. Recently, accumulating research focused on exploring the roles of those modifications in regulating tumorigenesis. Moreover, the dysregulation of histone modifications is supposed to have vital clinical significance. Numerous histone modifications have the potential to be prognostic biomarkers, monitoring response of therapy, early diagnostic markers. Herein, we review the recent advances of histone modifications involving development of gastric cancer. KEY WORDS: Acetylation, gastric cancer, histone modification, methylation, phosphorylation
INTRODUCTION The occurrence and development of tumor are resulted from genetic and epigenetic dysregulation. [1‑3] Genetic variations, such as gene mutation, translate, transpositions, are always recognized as the principal factor of tumor development. Accumulating evidence demonstrated that the epigenetic changes caused by the microenvironment also played important roles.[4,5] The epigenetic is referred to the changes of heritable gene expression and regulation without sequence rearrangement.[6] At present, DNA methylation, histone modification, genomic imprinting, chromosome remodeling, miRNAs are known as epigenetic changes. Among those events, high methylation of CpG islands in the promoter of tumor suppressor genes is the most common.[7] Moreover, some epigenetic changes are associated with chromosome, of which are core histone proteins modification (namely histone modification). The principal of histone modification is that the N terminus of core proteins (H2A, H2B, H3, H4) are modified with multiple covalent modification after translation, such as acetylation, methylation, and phosphorylation. [8] As the discovery of a large number of histone modification enzymes and the proposed of “histone codon”,[9] histone modification is suggested not only to regulate normal physiological function, such as DNA replication, translation, or repair, but also to involve in tumor development. In view of this, more and more attentions had been focused on histone modification. Numerous studies have explored the changes in multiple kinds of cancer, such as prostatic cancer, lung cancer, renal cancer, C240
breast cancer, ovarian cancer, and pancreatic cancer. [10,11] More importantly, those changes indicated pivotal clinical significance. In addition, a lot of the catalytic enzyme of histone were found to have high activities in tumor.[11] Gastric cancer was ranked as the top morbidity and mortality rates. The investigations on gastric cancer histone modification would promote understanding the mechanism of gastric cancer development. [3] Moreover, those effects would improve diagnosis or therapy of gastric cancer. In this review, we conclude and discuss the recent progress of histone modifications involving development of gastric cancer.
Wen‑Yan Yang, Jing‑Liang Gu, Tian‑Min Zhen Key Laboratory of Medical Library, Shandong Institute of Medicine and Health Information, Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan 250062, China For correspondence: Prof. Tian‑Min Zhen, Shandong Institute of Medicine and Health Information, Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan 250062, China. E‑mail: tmzhen@sina. com
CHROMATIN STRUCTURE Eukaryotic chromosome is complex and constituted with DNA, histone, nonhistone molecules. There are two basic forms, heterochromatin that exist in condensed chromosome with transcription inhibited, and euchromatin that was the loos chromosome with active transcription.[12] The basic units of chromatin are nucleosome, core granules are composed of histone octamer (core histones), which contains two H2A, H2B, H3 and H4, and about 146 bp DNA that intertwined on the core histones. Furthermore, the core histones would interact through H1 to form chromatin. Every core histone contained a spherical domain and an exposed N terminal. After finishing histone translation, the N terminal would be modified with acetylation, methylation, phosphorylation, ubiquitination, sumoylation, adenosine diphosphate (ADP) glycosylation, or carbonylation Fuchs et al. [13] Histone modifications can regulate structures and
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Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
Yang, et al.: Histone modification in gastric cancer
functions of chromosome by two ways. Firstly, histones are enriched with positively charged arginine and lysine, which can tightly bind to DNA with a negative charge. Thus, histone modifications would affect the interaction between DNA and histone. Secondly, histone modification prone to produce binding surface of protein recognized motif. It recruited special protein complex to the binding surface. Thus, histone modification could determine active or inactive of chromosome by changing its structures, as results, to control cellular physical pathways.
promotes the interaction between transcription factors or synergy transcription factors and DNA chains. Thereafter, the histone acetylation activates specific gene transcription. On the contrary, HDAC could remove the acetyls from histone Lys and recover the positive charge, thus the positively charged Lys increase the attraction between negatively charged DNA chain and histone, preventing transcriptional regulatory elements binding to promoters and inhibiting the transcription. In generally, the active region of nucleosomal histone is always under hyper‑acetylation. Therefore, the acetylation is related to gene activation while deacetylation means gene silence.[20,21]
HISTONE MODIFICATION It has been known that there were nine histone modifications, acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP glycosylation, carbonylation, proline isomerization, and propionylation.[13,14] Currently, numerous studies had focused on exploring the roles of acetylation, methylation, and phosphorylation, moreover, acetylation and methylation of H3 or H4 were most commonly.[15,16] These histone modifications can combine with each other. For instance, histone methylation in lysine includes single, double, three methylation.[17] Furthermore, histone modification can regulate and control chromosome structures to affect DNA functions. Thus, histone modification may be fine mechanisms of gene expression orchestra. Histone acetylation Histone acetylation is a reversible process of dynamic balance in healthy physiological process. Histone acetyltransferase (HATs) and histone deacetylase (HDACs) are the most important enzymes to maintain balance between acetylation and deacetylation. According to cellular location and functions, HATs could be divided into two types: Type A in the nucleus, which exhibits function on regulating gene transcription; while, type B in cytoplasm catalyzes acetylation of nonhistone proteins. HATs mainly include GNAT, MYST, MOZ/YBF2/SAS2/ TIP60 and CBP/p300 families. All these three families exist in complexes forms, such as GCN5, PCAG, MORF, CBP/p300. The complexes would interact and effect each other. Thereby, those interactions could play important roles in cell development, differentiation, or cycles. Currently, HDACs are divided into four Class from I–IV; I includes 1, 2, 3, 8; II includes 4–7, 9, 10; III includes SITR1‑7; IV includes HDAC11, which contains some characteristics of I and II.[18] HDACs I mainly regulate histone acetylation and chromosome structures; HDACs II and IV probably catalyze nonhistone deacetylation in the cytoplasm.[19] The members of SIRTs family regulate cell senescence, DNA repair, cell cycles.[11] The histone acetylation is the process that HATs transfer acetyl from acetyl coenzyme A to the specific e‑amino of Lys residual in the amino terminal of core proteins. The positive charge is removed, while DNA molecular with a negative charge is in favor of unfolding the DNA conformation and loosening nucleosome. Furthermore, the loosened structure Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
Histone methylation Histone protein now divides into five classes: H1, H2A, H2B, H3, and H4. Methylation sites are often found in lysine or arginine of H3 or H4. In special, both single and double methylations can be found in arginine while there are one, two, and three methyl in lysine. Histone methyltransferases (HMTs) include histone arginine methyl transferase (HRMTs) and histone lysine methylation transferase (HKMTs). Furthermore, HRMTs comprise two types: Type I catalyzes arginine single methylation and asymmetric double methylation; Type II enzyme catalyzes arginine single or symmetric double methylation.[22] HKMTs are composed with lysine specific SET region HMTs and without lysine SET HMTs.[23,24] Previously, methylation was thought as irreversible progress. After the finding of fist histone demethylase (HDMS), LSD1,[25] the histone methylation were proved to be one of reversible program, just like acetylation. Thereafter, a large amount of HDMS were identified, such as JHDM1A, JMJD2/KDM4.PUT1. However, different from acetylation, the HDMS functions are variant with different sites and types, for example, H3K9 and H4K20 could inhibit gene expression while H3K4, H3K36, and H3K79 could activate gene expression. In addition, the single methylation of H3K27 could active gene expression, while H3K37 double or trimethylation inhibit gene expression. Histone phosphorylation Histone phosphorylation is adding PO4 residual to terminus of histone. This reversible modification often happened in serine, threonine and tyrosine. The histone phosphorylation changes chromosome structures and regulates the interaction with transcription factors to affect gene transcription. As well as, different phosphorylations are related with variously cellular process such as transcription, mitosis, apoptosis, DNA repair. Up to now, the histone H3 phosphorylation has been extensively explored. Moreover, series of conservative phosphorylated regions were identified (such as T3, S10, T11, S28, T45). The serine, threonine and tyrosine of H1, H2A, H2B and H4 were also prone to be phosphorylated. The phosphorylated processes are catalyzed by various kinases. For instance, DNA damage signaling pathways induce histone H2AX to be phosphorylated and which mainly dependent on triphosphate inositol kinase related kinase. [26] Mst1 kinase could catalyze phosphorylation of H2BS14, which play important roles in cell apoptosis.[27] The transcription C241
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activation related phosphorylation of histone H3S10 and H3S28 were catalyzed by Aurora kinase.[28] MSK/RSK/Jil‑1 kinase family could mediate H3S10 phosphorylation to regulate gene expression.[28] Regarding to function, histone phosphorylation mainly regulates gene transcriptions in related signaling pathways. Mahadevan et al.[29] found that the fast phosphorylation of H3 always accompanied with activation of c‑fos and c‑jun in 1991. After that, more and more evidence demonstrated that the phosphorylation of H3 Ser10 played extremely important roles during activating transcription in eukaryotes.[28] Protein kinase A can mediate H3 phosphorylation on serine 10, which is associated with transcriptional activation of ERK‑mitogen‑activated protein kinase (MAPK) signaling pathway and c‑fos. [30] Indirectly immune location assays also proved that ERK‑MAPK pathway could result in multiple sites H3 phosphorylation, among of them, some phosphorylated H3 might associate with quick activations of genes involving in ERK‑MAPK pathway.[31] In addition, H3 Ser10 phosphorylation can initiate cellular mitosis and promote chromatic aggregation at early G2 stage.[32‑34]
regions. It is demonstrated that histone H4 had a significant low acetylation levels in gastric tissue. Moreover, the acetylation was associated with tumor stage, invasion, and lymphatic metastasis.[46] Recently, Kang et al.[47] identified that HDAC4 could facilitate gastric cancer progression by p21 repression. Park et al.[48] showed that the acetylation level of H3K9 in gastric cancer tissues was related with WHO grade and Laruen classification. Meanwhile, H4K16 acetylation was unrelated with any clinical parameters. Mutze et al.[49] discovered that HDAC1 and HDAC2 had high levels in gastric cancer tissues, and HDAC1 could be used as one of the potential risk stratification factors for patients who are sensitivity to chemotherapy.
Histone modification affected the important physical functions. Thus, the dysregulation would cause abnormal gene expressions to change their physiological functions, leading to carcinogenesis.[3,42]
Histone methylation and gastric cancer The researches about histone methylation on gastric cancer mainly focused on H3 and H4.[50] Park et al.[48] discovered that the triple methylation on H3K9 was associated with tumor stage, lymphovascular invasion, recurrence, and overall survival rates. Multivariate survival analysis revealed that the triple methylation of H3K9 was independent prognostic factor of gastric cancer.[48] Zhang et al.[51] analyzed triple methylation between gastric cancerous and matched adjacent normal tissues by chromatin immunoprecipitation linked to the microarray (ChIP‑chip) approach. They proved that there were 128 genes in total with significantly differences in H3K27 triple methylation on CpG islands between cancerous and normal tissues. The work from Gao et al.[52] also provide evidence for these. These might help to illustrate the mechanism of gastric cancer development. Meng et al.[53] identified that low H3K9 acetylation, H3K9 di‑methylation and DNA methylation in the promoter regions of tumor suppressor gene p16 would in combination decrease expression of p16. Moreover, 5‑aza‑2’‑deoxycytidine (5‑Aza‑dC) inhibited H3k9 di‑methylation and DNA methylation, and increased H3K9 acetylation to promote p16 expression. Furthermore, the enzyme that the catalyzed methylation also be changed.[53] Matsukawa et al.[54] demonstrated that EZH2 was over‑expressed in gastric cancer and associated with tumor size, invasion depth, vascular invasion, lymph node metastasis, and clinical stages. Multivariate survival analysis suggested that high levels of EZH2 meant poor prognosis. Fujii and Ochiai.[55] discovered that EZH2 caused H3K27 methylation in the promoter of E‑cadherin, thus down‑regulated its expression. This would be the reason that over‑expression EZH2 related with poor prognosis.
Histone acetylation and gastric cancer A large number of studies about histone acetylation on malignant tumor have been conducted.[43] However, more extensively exploration is still needed on its roles in gastric cancer. Mitani et al.[44] found that tumor suppressor gene P21 WAP1/CIP1 with low levels of H3 acetylation on promoter resulted in its down‑regulation. Xia et al.[45] identified that Helicobacter pylori increased expression of P21 WAP1/CIP1 by maintaining high acetylation levels of H4 on its promoter
Histone phosphorylation and gastric cancer There were fewer reports about histone phosphorylation on gastric cancer. Takahashi et al.[56] revealed that high levels of H3 phosphorylation were found in gastric cancer. Furthermore, they found that H3 phosphorylation was useful for the prediction of prognosis in gastric cancer and was associated with histological types, vascular invasion, and lymphatic metastasis. Fehri et al.[57] proved that H. pylori decreased phosphorylation levels of H3S10 and H3T3 to regulate cell
The relationships among different histone modifications The histone modifications involved gene activation or inhibition are not independent, but interactive, including synergy and antagonism. For example, H3 S10 phosphorylation promotes H3K14 acetylation and H3K4 methylation. Moreover, it would inhibit H3K9 methylation [35,36] and H2BK123 ubiquitination and mediate H3K4 or H3K79 methylation translated activation.[37] However, the H3K9 methylation prevents H3S10 phosphorylation and gene transcription, while, H3K9 acetylation is related with transcription activation.[36] In addition, histone modifications are also related to epigenetic, important pathways. For instance, histone modification and DNA methylation could cooperate to silence some antitumor gene.[38] MiRANs could regulate epigenetic modification by targeting to catalyzing enzyme (enhancer of zeste homolog 2 [EZH2]) and DNA methylase (DNAMT3A, DNMT3B).[39,40] The triple methylation of histone H3K27 was catalyzed by EZH2 and related with Ras, NF‑κB, SATA, Wnt/β‑catenin pathways.[41] HISTONE MODIFICATION AND GASTRIC CANCER
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cycles. This might be one of the novel important mechanisms of H. pylori inducing the development of gastric cancer. THE CLINICAL APPLICATION OF HISTONE MODIFICATION Similar with other epigenetic, the histone modifications were reversible progresses, providing principle evidence for tumor‑targeted therapy. So far, accumulating studies emphasized on histone deacetylation and methylation inhibitors, such as trichostatin A (TSA), SAHA, and DZNep, BIX‑01294.[58‑62] Among them, SAHA had been approved by US Food and Drug Administration to apply in clinical for the treatment of cutaneous T‑cell lymphomas.[62] During carcinogenesis and development, various epigenetic modifications interacted with catalytic enzymes. The designed inhibitors on a series epigenetic modifications showed adverse effects in the treatment of tumors. For instance, DNA methylation inhibitors 5‑aza, 5‑aza‑dC and etc., are insufficient in specificity and stability in vivo, with unsatisfactory clinical benefits. Although HDAC could induce tumor cell cycle arrest, differentiation, or apoptosis. Moreover, some agents, such as TSA, SAA, MS‑275, have been tested in phase I and II clinical trials.[59,63‑67] However, HDAC shows nonsignificantly difference in comparing with DNA methylation inhibitors. Therefore, combined application of multiple inhibitors has become a hot‑topic for the clinical investigations of histone modification inhibitors. It is reported that combined DNMT and HDAC inhibitors could activate expression of tumor repress genes, including MLH1, TIMP3, CDKN2B, CDKN2A, and ARHI, promoting tumor cell apoptosis.[68‑72] Manuyakorn et al.[73] found that the pancreatic cancer patients with low levels di‑methylation of H3K4, H3K9, and acetylation of H3K18 were not benefit from 5‑fluoouracil (5‑FU) chemotherapy. It is supposed that the combination of acetylated and methylated inhibitors might improve histone acetylation and thus improve prognosis of patients with pancreatic cancer. Histone modification could be served as biomarkers for prognosis, therapy response and others.[74] Seligson et al.[75] identified that low levels of histone modification had a poor prognosis in prostatic cancers patients with surgical resection of primary tumor lesions. Moreover, in comparing with other clinical factors, histone modification was the only independent prognostic factor. Some studies revealed that multiple kinds of histone modification could be used as independent prognostic markers for prostatic cancer, lung cancer, renal cancer, pancreatic cancer, or ovarian cancer. Manuyakorn et al.[73] also explored that H3K4 and H3K9 di‑methylation, H3K18 acetylation, could serve as potential biomarkers response to gemcitabine treatment on pancreatic cancer. They proved that pancreatic cancer patients with low acetylation of histone were more favorable to gemcitabine treatment with higher over survival rates in the comparison with 5‑FU. Broeck et al.[76] found that H4K20 methylations were lost in nonsmall cell lung cancer precancerous lesion. Therefore, H4K20 methylation might be used as monitor biomarkers for nonsmall cell lung Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 3- 2014
cancer. Deligezer et al.[77] discovered that H3K9 methylation were found in plasma by chromatin immunoprecipitation. All of those evidences provided the potential that histone modifications could be used as tumor markers in practice. CONCLUSION In a word, histone modifications were part of epigenetic and attracted a lot of attention on its roles in carcinogenesis and tumor development. However, the clinical application of histone modifications was limited in overall levels of modification. Until now, the clinical application value of some specific promoter histone modifications still undefined. In addition, malignant tumor was disease with obviously heterogeneity. Thus, it still need to be extensively explored the roles of histone modification. ACKNOWLEDGEMENTS This project is supported by Science and Technology Department of Shandong Province.
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