Document Detail

H3K27 trimethylation is an early epigenetic event of p16INK4a silencing for regaining tumorigenesis in fusion reprogrammed hepatoma cells.
MedLine Citation:
PMID:  20382980     Owner:  NLM     Status:  MEDLINE    
Stable epigenetic silencing of p16(INK4a) is a common event in hepatocellular carcinoma (HCC) cells, which is associated with abnormal cell proliferation and liberation from cell cycle arrest. Understanding the early epigenetic events in silencing p16(INK4a) expression may illuminate a prognostic strategy to block HCC development. Toward this end, we created a reprogram cell model by the fusion mouse HCC cells with mouse embryonic stem cells, in which the ES-Hepa hybrids forfeited HCC cell characteristics along with reactivation of the silenced p16(INK4a). HCC characteristics, in terms of gene expression pattern and tumorigenic potential, was restored upon induced differentiation of these reprogrammed ES-Hepa hybrids. The histone methylation pattern relative to p16(INK4a) silencing during differentiation of the ES-Hepa hybrids was analyzed. H3K27 trimethylation at the p16(INK4a) promoter region, occurring in the early onset of p16(INK4a) silencing, was followed by H3K9 dimethylation at later stages. During the induced differentiation of the ES-Hepa hybrids, H3K4 di- and trimethylations were maintained at high levels during the silencing of p16(INK4a), strongly suggesting that H3K4 methylation events did not cause the silencing of p16(INK4a). Our results suggested that the enrichment of H3K27 trimethylation, independent of H3K9 dimethylation, trimethylation, and DNA methylation, was an early event in the silencing of p16(INK4a) during the tumor development. This unique chromatin pattern may be a heritable marker of epigenetic regulation for p16(INK4a) silencing during the developmental process of hepatocellular carcinogenesis.
Jia-Yi Yao; Lei Zhang; Xin Zhang; Zhi-Ying He; Yue Ma; Li-Jian Hui; Xin Wang; Yi-Ping Hu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-07     Completed Date:  2010-06-29     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18828-37     Citation Subset:  IM    
Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
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MeSH Terms
Carcinoma, Hepatocellular / metabolism*
Cell Differentiation
Cell Line, Tumor
Chromatin / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
DNA Methylation*
Embryonic Stem Cells / cytology
Epigenesis, Genetic*
Flow Cytometry
Gene Silencing*
Histones / chemistry*,  metabolism
Liver Neoplasms / metabolism*
Grant Support
Reg. No./Substance:
0/Chromatin; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Histones

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