Autophagic effect of SAM-competitive EZH2 inhibitors on cancer cells

Tsang Pai Liu, Pei-Ming Yang

Research output: Contribution to journalArticle

Abstract

Enhancer of zeste homolog 2 (EZH2) is an epigenetic enzyme that mediates gene silencing through tri-methylation of histone H3 lysine 27 (H3K27-me3). Because overexpression of EZH2 in tumors is frequently found, its inhibition has been viewed as a novel anticancer strategy. Numerous small-molecule EZH2 inhibitors have been developed in recent years. S-adenosyl-L-homocysteine (SAH) hydrolase inhibitor, such as 3-Deazaneplanocin A (DZNep), and S-adenosyl-L-methionine (SAM)-competitive inhibitor, such as GSK343, represent two major types of EZH2 inhibitors. DZNep depletes EZH2 protein through the proteasome-dependent pathway. GSK343 directly inhibits the enzyme activity through competing the co-factor SAM. Our results demonstrate that GSK343, but not DZNep, induces apoptosis and autophagic cell death and enhances drug sensitivity in cancer cells. Our study shows, for the first time, that SAM-competitive EZH2 inhibitors are potent autophagy inducers, representing a novel anticancer mechanism for EZH2 inhibitors. Although autophagy is generally seen as a cytoplasmic event, recent studies reveal a transcriptional and epigenetic network that regulates autophagy. In our study, EZH2 seems not to be sufficient to initiate autophagy. However, our results provide some clues that support the promoting role of EZH2 in autophagy, which will be discussed in the highlight.
Original languageEnglish
Pages (from-to)e551-e551
JournalCancer Cell & Microenvironment
Volume2
Publication statusPublished - 2015

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