P38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma.

ABSTRACT: Enhancer of zeste homolog 2 (EZH2) mediates epigenetic gene silencing via tri-methylation of histone H3 lysine 27 (H3K27-me3). Increased expression of EZH2 is frequently detected in various cancers including hepatocellular carcinoma (HCC), which is associated with the silencing of tumor suppressor genes. S-adenosyl-L-methionine (SAM)-competitive EZH2 inhibitors fall into the major category of EZH2 inhibitors for cancer therapy. In this study, microarray analyses found that induction of genes related to cholesterol homeostasis is a common effect of SAM-competitive EZH2 inhibitors in cancer cells. As a representative, GSK343 induced lipid accumulation which promoted cancer cell survival. GSK343 selectively activated sterol regulatory element-binding protein 2 (SREBP2), but not SREBP1, in HCC

SUBMITTER: Yang PM 

PROVIDER: S-EPMC6834481 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature