EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells

Yao-Yu Hsieh, Hsiang Ling Huang, Pei-Ming Yang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Enhancer of zeste homolog 2 (EZH2) has been emerged as novel anticancer target. Various EZH2 small-molecule inhibitors have been developed in recent years. A major class of EZH2 inhibitors are S-adenosyl-L-methionine (SAM)-competitive inhibitors, such as EPZ005687, EI1, GSK126, UNC1999 and GSK343. Autophagy, a physiological process of self-digestion, is involved in the turnover of proteins or intracellular organelles. It can serve as cytoprotective or cytotoxic function in cancer. Our previous study has found that UNC1999 and GSK343 are potent autophagy inducers. In this study, the underlying molecular mechanisms were further investigated. Our results showed that UNC1999 and GSK343 transcriptionally upregulated autophagy of human colorectal cancer (CRC) cells through inducing LC3B gene expression. Besides, UNC1999/GSK343-induced autophagy was partially dependent on ATG7 but independent to EZH2 inhibition. Microarray and PCR array analyses identified that UNC1999 and GSK343 also induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UNC1999/GSK343-induced ER stress/UPR contributed to the survival of cancer cells, which was opposite to UNC1999/GSK343-induced autophagy that promoted cell death.

Original languageEnglish
Pages (from-to)1661-1680
Number of pages20
JournalAmerican Journal of Cancer Research
Volume6
Issue number8
Publication statusPublished - 2016

Fingerprint

Unfolded Protein Response
Autophagy
Colorectal Neoplasms
Up-Regulation
Endoplasmic Reticulum Stress
Heat-Shock Proteins
Physiological Phenomena
S-Adenosylmethionine
Enhancer of Zeste Homolog 2 Protein
GSK343
Organelles
Digestion
Neoplasms
Cell Survival
Cell Death
Gene Expression
Polymerase Chain Reaction

Keywords

  • Autophagy
  • Colorectal cancer
  • ER stress
  • EZH2
  • Unfolded protein response

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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abstract = "Enhancer of zeste homolog 2 (EZH2) has been emerged as novel anticancer target. Various EZH2 small-molecule inhibitors have been developed in recent years. A major class of EZH2 inhibitors are S-adenosyl-L-methionine (SAM)-competitive inhibitors, such as EPZ005687, EI1, GSK126, UNC1999 and GSK343. Autophagy, a physiological process of self-digestion, is involved in the turnover of proteins or intracellular organelles. It can serve as cytoprotective or cytotoxic function in cancer. Our previous study has found that UNC1999 and GSK343 are potent autophagy inducers. In this study, the underlying molecular mechanisms were further investigated. Our results showed that UNC1999 and GSK343 transcriptionally upregulated autophagy of human colorectal cancer (CRC) cells through inducing LC3B gene expression. Besides, UNC1999/GSK343-induced autophagy was partially dependent on ATG7 but independent to EZH2 inhibition. Microarray and PCR array analyses identified that UNC1999 and GSK343 also induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UNC1999/GSK343-induced ER stress/UPR contributed to the survival of cancer cells, which was opposite to UNC1999/GSK343-induced autophagy that promoted cell death.",
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AU - Huang, Hsiang Ling

AU - Yang, Pei-Ming

PY - 2016

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AB - Enhancer of zeste homolog 2 (EZH2) has been emerged as novel anticancer target. Various EZH2 small-molecule inhibitors have been developed in recent years. A major class of EZH2 inhibitors are S-adenosyl-L-methionine (SAM)-competitive inhibitors, such as EPZ005687, EI1, GSK126, UNC1999 and GSK343. Autophagy, a physiological process of self-digestion, is involved in the turnover of proteins or intracellular organelles. It can serve as cytoprotective or cytotoxic function in cancer. Our previous study has found that UNC1999 and GSK343 are potent autophagy inducers. In this study, the underlying molecular mechanisms were further investigated. Our results showed that UNC1999 and GSK343 transcriptionally upregulated autophagy of human colorectal cancer (CRC) cells through inducing LC3B gene expression. Besides, UNC1999/GSK343-induced autophagy was partially dependent on ATG7 but independent to EZH2 inhibition. Microarray and PCR array analyses identified that UNC1999 and GSK343 also induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UNC1999/GSK343-induced ER stress/UPR contributed to the survival of cancer cells, which was opposite to UNC1999/GSK343-induced autophagy that promoted cell death.

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