S-adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells

Tsang Pai Liu, Hsiang Ling Lo, Li Shan Wei, Heidi Hao Yun Hsiao, Pei Ming Yang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.

Original languageEnglish
Pages (from-to)139-147
Number of pages9
JournalAnti-Cancer Drugs
Volume26
Issue number2
DOIs
Publication statusPublished - 2015

Fingerprint

S-Adenosylmethionine
Autophagy
Pharmaceutical Preparations
Neoplasms
Antineoplastic Agents
histone methyltransferase
Enhancer of Zeste Homolog 2 Protein
GSK343
Hepatocellular Carcinoma
3-deazaneplanocin
Enzymes

Keywords

  • Autophagy
  • Cancer
  • EZH2
  • S-adenosyl-L-methionine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research
  • Oncology

Cite this

S-adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells. / Liu, Tsang Pai; Lo, Hsiang Ling; Wei, Li Shan; Hsiao, Heidi Hao Yun; Yang, Pei Ming.

In: Anti-Cancer Drugs, Vol. 26, No. 2, 2015, p. 139-147.

Research output: Contribution to journalArticle

@article{53c43f6e22634322be136ddca728f255,
title = "S-adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells",
abstract = "The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.",
keywords = "Autophagy, Cancer, EZH2, S-adenosyl-L-methionine",
author = "Liu, {Tsang Pai} and Lo, {Hsiang Ling} and Wei, {Li Shan} and Hsiao, {Heidi Hao Yun} and Yang, {Pei Ming}",
year = "2015",
doi = "10.1097/CAD.0000000000000166",
language = "English",
volume = "26",
pages = "139--147",
journal = "Anti-Cancer Drugs",
issn = "0959-4973",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - S-adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells

AU - Liu, Tsang Pai

AU - Lo, Hsiang Ling

AU - Wei, Li Shan

AU - Hsiao, Heidi Hao Yun

AU - Yang, Pei Ming

PY - 2015

Y1 - 2015

N2 - The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.

AB - The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.

KW - Autophagy

KW - Cancer

KW - EZH2

KW - S-adenosyl-L-methionine

UR - http://www.scopus.com/inward/record.url?scp=84937402450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937402450&partnerID=8YFLogxK

U2 - 10.1097/CAD.0000000000000166

DO - 10.1097/CAD.0000000000000166

M3 - Article

VL - 26

SP - 139

EP - 147

JO - Anti-Cancer Drugs

JF - Anti-Cancer Drugs

SN - 0959-4973

IS - 2

ER -