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Epigenetic Mechanisms and Hepatocellular Carcinoma

Year 2016, Volume: 8 Issue: 3, 29 - 35, 01.12.2016

Abstract

Epigenetic mechanisms provide heritable changes in gene expression and chromatin organization in the eukaryotic cells. Abnormal epigenetic mechanisms particularly play a key role in many different diseases, such as hepatocellular carcinoma. Hepatocellular carcinoma HCC is both genetic and epigenetic disease and is located in the third place in cancer related deaths worldwide. Hepatocarcinogenesis is constituted by a complex, multistep process. Epigenetic changes include aberrant DNA methylation, posttranslational histone modifications, aberrant expression of non-coding RNAs such as miRNAs, lnc-RNAs and chromatin remodeling. These mechanisms can affect directly the expression of oncogenes, tumor suppressor genes and other tumor-related genes and alter the pathways in cancer development. Many complex deregulation of miRNAs, lnc-RNAs long non-coding RNAs and piRNAs PIWI-interacting RNAs are dramatically involved in hepatocarcinogenesis, which target tumor suppressor genes. Furthermore, down-regulation of these genes in HCC is induced by promoter hypermethylation or posttranslational deregulation. The role of these epigenetic mechanisms in hepatocarcinogenesis provide new therapeutic approaches for HCC. In this review, the results of recent studies related with epigenetic mechanisms in the development of hepatocellular carcinoma have been summarized.

References

  • Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253–1257.
  • Center MM, Jemal A. International trends in liver can- cer incidence rates. Cancer Epidemiol Biomarkers Prev 2011;20:2362–2368
  • Herath N.I, Leggett B.A, MacDonald G.A. Review of ge- netic and epigenetic alterations in hepatocarcinogene- sis, J. Gastroenterol. Hepatol. 2006;15–21.
  • Vaissiere T, Sawan C, Herceg Z. Epigenetic interplay be- tween histone modifications and DNA methylation in gene silencing, Mutat. Res. 2008;659:40–48.
  • Frau M, Feo F.C, Feo F, Pascale R.M. New insights on the role of epigenetic alterations in hepatocellular carcino- ma. Journal of Hepatocellular Carcinoma 2014;1:65– 83.
  • You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012;22:9-20.
  • Calvisi D.F, Ladu S, Gorden A, Farina M, Lee J.S, Conner E.A, Schroeder I, Factor V.M, Thorgeirsson S.S. Mecha- nistic and prognostic significance of aberrant methyla- tion in the molecular pathogenesis of human hepatocel- lular carcinoma, J. Clin. Invest. 2007;117:2713–2722.
  • Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 2005;25:16– 27.
  • Bird AP. The relationship of DNA methylation to cancer. Cancer Surv. 1996;28:87–101.
  • Bestor TH, Ingram VM. Two DNA methyltransferases from murine erythroleukemia cells: purification, se- quence specificity, and mode of interaction with DNA. Proc Natl Acad Sci U S A. 1983;80(18):5559–5563.
  • Okano M, Bell DW, Haber DA, Li E. DNA methyltrans- ferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–257.
  • Bell AC, Felsenfeld G. Methylation of a CTCF-depend- ent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405(6785):482–485.
  • Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990;1(5):228–237.
  • Pascale RM, Simile MM, De Miglio MR. Chemopreven- tion by S-adenosyl-L-methionine of rat liver carcinogen- esis initiated by 1,2-dimethylhydrazine and promoted by orotic acid. Carcinogenesis. 1995;16(2):427–430.
  • Lu SC, Mato JM. Role of methionine adenosyltrans- ferase and S-adenosylmethionine in alcohol-associated liver cancer. Alcohol. 2005;35(3):227–234.
  • Yang B, Guo M, Herman JG, Clark DP. Aberrant promot- er methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163:1101– 1107.
  • Jicai Z, Zongtao Y, Jun L, Haiping L, Jianmin W, Lihua H. Persistent infection of hepatitis B virus is involved in high rate of p16 methylation in hepatocellular carcinoma. Mol Carcinog 2006;45:530–536.
  • Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ. Si- lencing of GSTP1 gene by CpG island DNA hypermeth- ylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res 2002;8:1087–1092.
  • Lambert MP, Paliwal A, Vaissiere T, Chemin I, Zoulim F, Tommasino M. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J Hepatol 2011;54:705– 715.
  • Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY. High frequency of promoter hypermethylation of the RASSF1A and p16 genes and its relationship to afl atoxin B1-DNA adducts level in human hepatocellular carcinoma. Mol Carcinogenesis 2002;35:85–92.
  • Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC. Genome-wide hypomethylation in hepatocellular car- cinogenesis. Cancer Res 2001;61:4238–4243.
  • Allis C.D, Jenuwein T, Reinberg D, Caparros M.L Epige- netics. Cold Spring Harbor Laboratory Press. 2007.
  • Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–428.
  • Kouzarides T. Chromatin modifi cations and their func- tion. Cell 2007;128:693–705.
  • Herceg Z, Paliwal A. Epigenetic mechanisms in hepa- tocellular carcinoma: how environmental factors infl uence the epigenome. Mutat Res 2011;727:55–61.
  • Schneider R, Grosschedl R. Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes Dev 2007;21:3027–3043.
  • He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z. High expres- sion of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol 2012;43:1425–1435.
  • Cai MY, Hou JH, Rao HL, Luo RZ, Li M, Pei XQ. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med 2011;17:12–20.
  • Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tana- ka Y. Alterations of DNA methylation and histone mod- ifi cations contribute to gene silencing in hepatocellular carcinomas. Hepatol Res 2007;37: 974–983.
  • Sistayanarain A, Tsuneyama K, Zheng H, Takahashi H, Nomoto K, Cheng C. Expression of Aurora-B kinase and phosphorylated histone H3 in hepatocellular carcino- ma. Anticancer Res 2006;26:3585–3593.
  • Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Car- cinogenesis 2010;31: 27–36.
  • Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M. SMYD3 encodes a histone methyltransferase in- volved in the proliferation of cancer cells. Nat Cell Biol 2004;6:731–740 112.
  • Mattick J.S, and Makunin I.V. Non-coding RNA. Hum. Mol. Genet. 2006;15 (1):17-29.
  • Bartel DP. MicroRNAs: genomics, biogenesis, mecha- nism, and function. Cell 2004;116:281–297.
  • Negrini M, Gramantieri L, Sabbioni S, Croce CM. microR- NA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem 2011;11:500–521.
  • Parasramka M.A, Maji S, Matsuda A, Yan I.K, Patel T. Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacology & Therapeu- tics. 2016;161:67–78.
  • Kevin W. Ng, Anderson C, Erin A. Marshall, Brenda C. Minatel, Katey S. S. Enfield, Heather L. Saprunoff, Wan L. Lam and Victor D. Martinez. Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Molecular Cancer 2016;15:5.
  • Endo M,Yasui K, Zen Y, Gen Y, Zen K, Tsuji K, Dohi O, Mit- suyoshi H,Tanaka S, Taniwaki M, Nakanuma Y, Arii S,Yo- shikawa Alterations of the SWI/SNF chromatin remodel- ling subunit-BRG1 and BRMin hepatocellular carcinoma. Liver International ISSN 2013;1478-3223.
  • Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD . Environmental epigenetics: prospects for studying epigenetic mediation of exposure response re- lationships. Hum Genet 2012;131: 1565–1589.
  • Winter J, Jung S, Keller S, Richard I, Diederichs G, Died- erichs S. Many roads to maturity: microRNA biogen- esis pathways and their regulation Nature Cell Biology 2009;11: 228 – 234.
  • Vignali M, Hassan A.H, Neely K.E, Workman J.L. ATP-De- pendent Chromatin-Remodeling Complexes. Mol. Cell. Biol. 2000;20:1899-1910.

Epigenetik Mekanizmalar ve Hepatosellüler Karsinoma

Year 2016, Volume: 8 Issue: 3, 29 - 35, 01.12.2016

Abstract

Epigenetik mekanizmalar ökaryotik hücrelerde gen ekspresyonunda ve kromatin organizasyonunda kalıtımsal değişiklikler sağlamaktadır. Epigenetik mekanizmalardaki değişimler; hepatosellüler karsinoma ve diğer birçok hastalıkta önemli rol oynamaktadır. Hepatosellüler karsinoma HCC hem genetik hem de epigenetik bir hastalıktır ve dünya çapında kanser sebepli ölümler arasında üçüncü sıradadır. Hepatokarsinogenez oldukça kompleks ve çok aşamalı bir süreçten oluşmaktadır. Epigenetik değişiklikler, anormal DNA metilasyonu, posttranslasyonel histon modifikasyonları, anormal kodlanmayan RNA miRNA, lnc-RNA gibi ekspresyonu ve kromatinin yeniden modellenmesini içermektedir. Bu mekanizmalar kanser gelişiminde onkogenlerin, tümör baskılayıcı genlerin ve diğer tümörle ilişkili genlerin ekspresyonunu ve yolakların değişimini doğrudan etkilemektedir. Pek çok kompleks miRNA, lnc-RNA uzun kodlanmayan RNA ve piRNA PIWI proteini ile ilişkili RNA regülasyon bozukluğu tümör baskılayıcı genleri hedef alarak dramatik bir şekilde hepatokarsinogeneze dahil olmaktadır. Ayrıca bu genlerin promotör hipermetilasyonu ya da posttranslasyonel regülasyon bozuklukları sebebiyle ekspresyonları azalmaktadır. Hepatokarsinogezde rol alan bu epigenetik mekanizmalar HCC için yeni terapötik yaklaşımlar sunmaktadır. Bu derlemede; hepatosellüler karsinoma oluşumunda etkili epigenetik mekanizmalar konusundaki güncel çalışmaların sonuçları özetlenmiştir.

References

  • Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253–1257.
  • Center MM, Jemal A. International trends in liver can- cer incidence rates. Cancer Epidemiol Biomarkers Prev 2011;20:2362–2368
  • Herath N.I, Leggett B.A, MacDonald G.A. Review of ge- netic and epigenetic alterations in hepatocarcinogene- sis, J. Gastroenterol. Hepatol. 2006;15–21.
  • Vaissiere T, Sawan C, Herceg Z. Epigenetic interplay be- tween histone modifications and DNA methylation in gene silencing, Mutat. Res. 2008;659:40–48.
  • Frau M, Feo F.C, Feo F, Pascale R.M. New insights on the role of epigenetic alterations in hepatocellular carcino- ma. Journal of Hepatocellular Carcinoma 2014;1:65– 83.
  • You JS, Jones PA. Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell 2012;22:9-20.
  • Calvisi D.F, Ladu S, Gorden A, Farina M, Lee J.S, Conner E.A, Schroeder I, Factor V.M, Thorgeirsson S.S. Mecha- nistic and prognostic significance of aberrant methyla- tion in the molecular pathogenesis of human hepatocel- lular carcinoma, J. Clin. Invest. 2007;117:2713–2722.
  • Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 2005;25:16– 27.
  • Bird AP. The relationship of DNA methylation to cancer. Cancer Surv. 1996;28:87–101.
  • Bestor TH, Ingram VM. Two DNA methyltransferases from murine erythroleukemia cells: purification, se- quence specificity, and mode of interaction with DNA. Proc Natl Acad Sci U S A. 1983;80(18):5559–5563.
  • Okano M, Bell DW, Haber DA, Li E. DNA methyltrans- ferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–257.
  • Bell AC, Felsenfeld G. Methylation of a CTCF-depend- ent boundary controls imprinted expression of the Igf2 gene. Nature. 2000;405(6785):482–485.
  • Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990;1(5):228–237.
  • Pascale RM, Simile MM, De Miglio MR. Chemopreven- tion by S-adenosyl-L-methionine of rat liver carcinogen- esis initiated by 1,2-dimethylhydrazine and promoted by orotic acid. Carcinogenesis. 1995;16(2):427–430.
  • Lu SC, Mato JM. Role of methionine adenosyltrans- ferase and S-adenosylmethionine in alcohol-associated liver cancer. Alcohol. 2005;35(3):227–234.
  • Yang B, Guo M, Herman JG, Clark DP. Aberrant promot- er methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol 2003;163:1101– 1107.
  • Jicai Z, Zongtao Y, Jun L, Haiping L, Jianmin W, Lihua H. Persistent infection of hepatitis B virus is involved in high rate of p16 methylation in hepatocellular carcinoma. Mol Carcinog 2006;45:530–536.
  • Zhong S, Tang MW, Yeo W, Liu C, Lo YM, Johnson PJ. Si- lencing of GSTP1 gene by CpG island DNA hypermeth- ylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res 2002;8:1087–1092.
  • Lambert MP, Paliwal A, Vaissiere T, Chemin I, Zoulim F, Tommasino M. Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake. J Hepatol 2011;54:705– 715.
  • Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY. High frequency of promoter hypermethylation of the RASSF1A and p16 genes and its relationship to afl atoxin B1-DNA adducts level in human hepatocellular carcinoma. Mol Carcinogenesis 2002;35:85–92.
  • Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC. Genome-wide hypomethylation in hepatocellular car- cinogenesis. Cancer Res 2001;61:4238–4243.
  • Allis C.D, Jenuwein T, Reinberg D, Caparros M.L Epige- netics. Cold Spring Harbor Laboratory Press. 2007.
  • Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–428.
  • Kouzarides T. Chromatin modifi cations and their func- tion. Cell 2007;128:693–705.
  • Herceg Z, Paliwal A. Epigenetic mechanisms in hepa- tocellular carcinoma: how environmental factors infl uence the epigenome. Mutat Res 2011;727:55–61.
  • Schneider R, Grosschedl R. Dynamics and interplay of nuclear architecture, genome organization, and gene expression. Genes Dev 2007;21:3027–3043.
  • He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z. High expres- sion of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol 2012;43:1425–1435.
  • Cai MY, Hou JH, Rao HL, Luo RZ, Li M, Pei XQ. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med 2011;17:12–20.
  • Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tana- ka Y. Alterations of DNA methylation and histone mod- ifi cations contribute to gene silencing in hepatocellular carcinomas. Hepatol Res 2007;37: 974–983.
  • Sistayanarain A, Tsuneyama K, Zheng H, Takahashi H, Nomoto K, Cheng C. Expression of Aurora-B kinase and phosphorylated histone H3 in hepatocellular carcino- ma. Anticancer Res 2006;26:3585–3593.
  • Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Car- cinogenesis 2010;31: 27–36.
  • Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M. SMYD3 encodes a histone methyltransferase in- volved in the proliferation of cancer cells. Nat Cell Biol 2004;6:731–740 112.
  • Mattick J.S, and Makunin I.V. Non-coding RNA. Hum. Mol. Genet. 2006;15 (1):17-29.
  • Bartel DP. MicroRNAs: genomics, biogenesis, mecha- nism, and function. Cell 2004;116:281–297.
  • Negrini M, Gramantieri L, Sabbioni S, Croce CM. microR- NA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem 2011;11:500–521.
  • Parasramka M.A, Maji S, Matsuda A, Yan I.K, Patel T. Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacology & Therapeu- tics. 2016;161:67–78.
  • Kevin W. Ng, Anderson C, Erin A. Marshall, Brenda C. Minatel, Katey S. S. Enfield, Heather L. Saprunoff, Wan L. Lam and Victor D. Martinez. Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Molecular Cancer 2016;15:5.
  • Endo M,Yasui K, Zen Y, Gen Y, Zen K, Tsuji K, Dohi O, Mit- suyoshi H,Tanaka S, Taniwaki M, Nakanuma Y, Arii S,Yo- shikawa Alterations of the SWI/SNF chromatin remodel- ling subunit-BRG1 and BRMin hepatocellular carcinoma. Liver International ISSN 2013;1478-3223.
  • Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD . Environmental epigenetics: prospects for studying epigenetic mediation of exposure response re- lationships. Hum Genet 2012;131: 1565–1589.
  • Winter J, Jung S, Keller S, Richard I, Diederichs G, Died- erichs S. Many roads to maturity: microRNA biogen- esis pathways and their regulation Nature Cell Biology 2009;11: 228 – 234.
  • Vignali M, Hassan A.H, Neely K.E, Workman J.L. ATP-De- pendent Chromatin-Remodeling Complexes. Mol. Cell. Biol. 2000;20:1899-1910.
There are 41 citations in total.

Details

Primary Language Turkish
Journal Section Collection
Authors

Rumeysa Doğan This is me

Ranan Gülhan Aktaş This is me

Publication Date December 1, 2016
Published in Issue Year 2016 Volume: 8 Issue: 3

Cite

Vancouver Doğan R, Aktaş RG. Epigenetik Mekanizmalar ve Hepatosellüler Karsinoma. Maltepe tıp derg. 2016;8(3):29-35.