Abstract
Purpose
It has been indicated that activated hepatic stellate cells (HSCs) play key roles on the pathogenesis of hepatocellular carcinoma (HCC). The purpose of the study was to investigate the potential mechanism in it.
Methods
Activation of HSCs, the expression of myocyte enhancer factor 2 (MEF2), class II histone deacetylases (II HDACs) and histone acetylation were analyzed in specimens of primary HCCs, cirrhotic and normal livers. Activated HSCs were identified using anti-a-smooth muscle actin (a-SMA) by Immunohistochemistry (IHC). The levels of expression of MEF2A, MEF2C and II HDACs mRNA and protein were measured by real time quantitative PCR and western blot (WB). Histone acetylation was assessed using anti-acetyl-histone H3, -H4 by WB and IHC. A P value < 0.05 was considered statistically significant.
Results
A-SMA positive activated HSCs were more prominent in HCCs and cirrhotic livers than in normal livers, accompanied by marked expression of MEF2A and MEF2C. The expression of MEF2A, MEF2C and II HDACs, both mRNA and protein, were much more enhanced in HCCs than those in cirrhotic and normal livers (P < 0.05). Histone H3 and H4 were hyperacetylated in HCCs compared with those in cirrhotic and normal livers (P < 0.05). The correlation coefficients between the expression of MEF2 and II HDACs, acetyl-histones were all beyond 0.5.
Conclusions
These data showed a potential molecular mechanism that activated HSCs participate in the pathogenesis of HCCs by overexpression of MEF2 and its consequent impact on histone hyperacetylation. Further investigations aimed at interfering MEF2 expression are needed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Archer SY, Hodin RA (1999) Histone acetylation and cancer. Curr Opin Genet Dev 9:171–174
Black BL, Olson EN (1998) Transcriptional control of muscle development by myocyte enhancer factor-2(MEF2) proteins. Annu Rev Cell Dev Biol 14:167–196
Borghi S, Molinari S, Razzini G, Parise F, Battini R, Ferrari S (2001) The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4. J Cell Sci 114:4477–4483
Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391:597–601
Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC et al (2005) Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci 102:3389–3394
Clayton AL, Hazzalin CA, Mahadevan LC (2006) Enhanced histone acetylation and transcription: a dynamic perspective. Mol Cell 23:289–296
Desmouliere A, Guyot C, Gabbiani G (2004) The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol 48:509–517
Forner A, Hessheimer AJ, Isabel Real M, Bruix J (2006) Treatment of hepatocellular carcinoma. Crit Rev Oncol Hematol 60:89–98
Geerts A (2001) History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21:311–335
Gotzmann J, Fischer AN, Zojer M, Mikula M, Proell V, Huber H et al (2006) A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene 25:3170–3185
Gruffat H, Manet E, Sergeant A (2002) MEF2-mediated recruitment of class II HDAC at the EBV immediate early gene BZLF1 links latency and chromatin remodeling. EMBO Rep 3:141–146
Han A, He J, Wu Y, Liu JO, Chen L (2005) Mechanism of recruitment of class II histone deacetylases by myocyte enhancer factor-2. J Mol Biol 345:91–102
Hassig CA, Fleischer TC, Billin AN, Schreiber SL, Ayer DE (1997) Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89:341–347
Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401
Kang J, Zhang D, Chen J, Lin C, Liu Q (2004) Involvement of histone hypoacetylation in Ni2+-induced bcl- 2 down-regulation and human hepatoma cell apoptosis. J Biol Inorg Chem 9:713–723
Kang J, Chen J, Shi Y, Jia J, Wang Z (2005a) Histone hypoacetylation is involved in 1,10-phenanthroline-Cu2+-induced human hepatoma cell apoptosis. J Biol Inorg Chem 10:190–198
Kang J, Chen J, Shi Y, Jia J, Zhang Y (2005b) Curcumin-induced histone hypoacetylation: the role of reactive oxygen species. Biochem Pharmacol 69:1205–1213
Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW et al (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443
Kim H, Lee JE, Kim BY, Cho EJ, Kim ST, Youn HD (2005) Menin represses JunD transcriptional activity in protein kinase C theta-mediated Nur77 expression. Exp Mol Med 37:466–475
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S et al (1998) Tissue microarrays for high-throughput molecular profiling of tumour specimens. Nat Med 4:844–847
Kurdistani SK, Tavazoie S, Grunstein M (2004) Mapping global histone acetylation patterns to gene expression. Cell 117:721–733
Liang T, Xu S, Yu J, Shen K, Li D, Zheng S (2005) Activation pattern of mitogen-activated protein kinases in early phase of different size liver isografts in rats. Liver Transplant 11:1527–1532
Lin Q, Schwarz J, Bucana C, Olson EN (1997) Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science 276:1404–1407
Ma K, Chan JK, Zhu G, Wu Z (2005) Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation. Mol Cell Biol 25:3575–3582
Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg ME (1999) Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286:785–790
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194–202
McKinsey TA, Zhang CL, Olson EN (2001) Control of muscle development by dueling HATs and HDACs. Curr Opin Genet Dev 11:497–504
McLaughlin F, La Thangue NB (2004) Histone deacetylase inhibitors open new doors in cancer therapy. Biochem Pharmacol 68:1139–1144
Mikula M, Proell V, Fischer AN, Mikulits W (2006) Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol 209:560–567
Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51
Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumor stroma in cancer. Nat Rev Cancer 4:839–849
Naya FJ, Olson E (1999) MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation. Curr Opin Cell Biol 11:683–688
Naya FJ, Black BL, Wu H, Bassel-Duby R, Richardson JA, Hill JA, Olson EN (2002) Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor. Nat Med 8:1303–1309
Ooi LP, Crawford DH, Gotley DC, Clouston AD, Strong RW, Gobe GC et al (1997) Evidence that “myofibroblast-like” cells are the cellular source of capsular collagen in hepatocellular carcinoma. J Hepatol 26:798–807
Park YN, Yang CP, Cubukcu O, Thung SN, Theise ND (1997) Hepatic stellate cell activation in dysplastic nodules: evidence for an alternate hypothesis concerning human hepatocarcinogenesis. Liver 17:271–274
Pinzani M, Rombouts K, Colagrande S (2005) Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 42(Suppl 1):S22–S36
Santos-Rosa H, Caldas C (2005) Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer 41:2381–2402
Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK et al (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266
Taddei A, Roche D, Bickmore WA, Almouzni G (2005) The effects of histone deacetylase inhibitors on heterochromatin: implications for anticancer therapy? EMBO Rep 6:520–524
Tokusashi Y, Asai K, Tamakawa S, Yamamoto M, Yoshie M, Yaginuma Y et al (2005) Expression of NGF in hepatocellular carcinoma cells with its receptors in non-tumor cell components. Int J Cancer 114:39–45
Wang X, Tang X, Gong X, Albanis E, Friedman SL, Mao Z (2004) Regulation of hepatic stellate cell activation and growth by transcription factor myocyte enhancer factor 2. Gastroenterology 127:1174–1188
Wen J, Zhang Y, Chen X, Shen L, Li GC, Xu M (2004) Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells. Biochem Pharmacol 68:323–331
Witz IP, Levy-Nissenbaum O (2006) The tumor microenvironment in the post-PAGET era. Cancer Lett 242:1–10
Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y (1996) A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382:319–324
Acknowledgment
This study was supported by the National Basic Research Program of China (2003CB515501).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by the National Basic Research Program of China; Grant number: 2003CB5155001; Science and Technology Bureau of Zhejiang Province Grant numbers: 2007C33075, 2007C24001.
Rights and permissions
About this article
Cite this article
Bai, X., Wu, L., Liang, T. et al. Overexpression of myocyte enhancer factor 2 and histone hyperacetylation in hepatocellular carcinoma. J Cancer Res Clin Oncol 134, 83–91 (2008). https://doi.org/10.1007/s00432-007-0252-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-007-0252-7