p38α/S1P/SREBP2 activation by the SAM-competitive EZH2 inhibitor GSK343 limits its anticancer activity but creates a druggable vulnerability in hepatocellular carcinoma.

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 cells. Inhibition of SREBP2 by siRNA reduced cell viability and enhanced the anticancer effect of GSK343. Cancer genomics analysis indicated that SREBP2 upregulation was associated with the poor overall survival of HCC patients. Mechanistically, GSK343-induced SREBP2 activation was unrelated to its original ability to compete with SAM and inhibit EZH2 activity. Instead, GSK343 activated SREBP2 in p38α- and site-1 protease (S1P)-dependent manners. Inhibition of p38α and S1P by SB-202190 and PF-429242, respectively, enhanced the in vitro anticancer activity of GSK343, thereby creating a vulnerability for treating HCC. AJCR