Overexpression of myocyte enhancer factor 2 and histone hyperacetylation in hepatocellular carcinoma.
OBJECTIVE
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.
Bai
Xueli
X
Key Laboratory of Multi-organ Transplantation of Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China.
Wu
Lihua
L
Liang
Tingbo
T
Liu
Zhiqiang
Z
Li
Junjian
J
Li
Donglin
D
Xie
Haiyang
H
Yin
Shengyong
S
Yu
Jun
J
Lin
Qi
Q
Zheng
Shusen
S
D000107:Acetylation / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis
D006657:Histones; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D006655:Histone Deacetylases