P-024 - The association between histone 3 lysine 27 trimethylation and liver fibrosis and cancer: relationship with methyltransferase

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Gastrointestinal Cancers
Translational Research
Presenter W.K. Bae
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors W.K. Bae, I.-. Chung, S.-. Cho, H.-. Shim
  • Chonnam National University Hwasun Hospital, Hwasun-Eup/KR

Abstract

Introduction

Epigenetic mechanisms of nuclear chromatin remodeling are increasingly recognized as crucial factors in hepatocellular carcinoma (HCC). Polycomb group members Ezh1 and Ezh2 are key epigenetic regulator of embryonic stem cell identity, but their role in liver metabolism and HCC is poorly understood.

Methods

To investigate the role of EZH2 and H3K27me3, mice were generated that carried Ezh1−/- and Ezh2fl/fl alleles and an Alb-Cre transgene. Mice were examined by injection of CCl4 and partial hepatectomy (PHx), and the RNA-seq and Chip-Seq analysis was determined. We checked the expression EZH2 and H3K27me3 status in 67 human HCC samples, and the gene expression by RNA-seq based on EZH2 expression.

Results

Only combined loss of EZH1 and EZH2 in mouse hepatocytes caused a depletion of global H3K27me3 marks and the specific loss over ∼1900 genes. Ezh1−/-, Ezh2fl/flAlb-Cre mice exhibited regenerative nodules and concomitant periportal fibrosis. In response to chronic treatment with CCl4, all mutant mice but none of the controls showed increased hepatic degeneration and reduced ability to proliferate. After PHx, mutant mice displayed increased liver injury and a blunted regenerative response. Genome-wide analyses identified 51 genes that had lost H3K27me3 marks and their expression was significantly increased. These genes were involved in regulation of cell survival, fibrosis, and proliferation. H3K27me3 levels and liver physiology were unaffected in mice lacking either EZH1 or EZH2. The high EZH2 expression was related with poor prognosis and the expression of EZH2 was not also correlated with H3K27me3 expression in human HCC. RNA-seq analysis showed up-regulation of cell cycle and DNA replication related genes in high EZH2 expressed HCCs.

Conclusion

This work demonstrates a critical redundancy of EZH1 and EZH2 in maintaining hepatic homeostasis, and non-canonical EZH2 function in HCC. This work demonstrates candidate EZH2 target genes in human HCC.