G9a and histone deacetylases are crucial for Snail2‐mediated E‐cadherin repression and metastasis in hepatocellular carcinoma

• DOI: 10.1111/cas.14173
• Publication Date: 2019-08-21T04:23:22Z
• Authors: Yue Hu; Yayuan Zheng; Mingrui Dai; Xueju Wang; Jiaxin Wu; Bin Yu; Haihong Zhang; Yinqiu Cui; Wei Kong; Hui Wu; Xianghui Yu
• Keywords: 0301 basic medicine; Carcinoma, Hepatocellular; Epithelial-Mesenchymal Transition; Liver Neoplasms; Down-Regulation; Acetylation; Original Articles; Azepines; Histone-Lysine N-Methyltransferase; Cadherins; Hydroxamic Acids; Methylation; Histone Deacetylases; Epigenesis, Genetic; 3. Good health; Histone Deacetylase Inhibitors; 03 medical and health sciences; Liver; Cell Movement; Histocompatibility Antigens; Disease Progression; Animals; Humans; Female

AbstractFunctional E‐cadherin loss, a hallmark of epithelial‐mesenchymal transition (EMT), is important for metastasis. However, the mechanism of Snail2 in hepatocellular carcinoma (HCC) EMT and metastasis remains unclear. Here, we showed that Snail2 was upregulated in primary HCC, and significantly increased during transforming growth factor‐β‐induced liver cell EMT. Snail2‐overexpressing and knockdown cell lines have been established to determine its function in EMT in HCC. H3K9 methylation was upregulated and H3K4 and H3K56 acetylation were downregulated at the E‐cadherin promoter in Snail2‐overexpressing cancer cells. Furthermore, Snail2 interacted with G9a and histone deacetylases (HDACs) to form a complex to suppress E‐cadherin transcription. Snail2 overexpression enhanced migration and invasion in HCC cells, whereas G9a and HDAC inhibition significantly reversed this effect. Moreover, Snail2 overexpression in cancer cells increased tumor metastasis and shortened survival time in mice, whereas G9a and HDAC inhibitors extended survival. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also suggests novel treatment strategies for HCC.