H3K27 trimethylation is an early epigenetic event of p16INK4a silencing for regaining tumorigenesis in fusion reprogrammed hepatoma cells.
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.
Yao
Jia-Yi
JY
Department of Cell Biology, Second Military Medical University, Shanghai 200433, China.
Zhang
Lei
L
Zhang
Xin
X
He
Zhi-Ying
ZY
Ma
Yue
Y
Hui
Li-Jian
LJ
Wang
Xin
X
Hu
Yi-Ping
YP
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D020868:Gene Silencing; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice
D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones
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