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

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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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          Author and article information

          Journal
          Am J Cancer Res
          American journal of cancer research
          2156-6976
          2156-6976
          2016
          : 6
          : 8
          Affiliations
          [1 ] PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia SinicaTaipei, Taiwan; Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Meidcal UniversityNew Taipei City, Taiwan.
          [2 ] PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia SinicaTaipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei, Taiwan.
          Article
          5004071
          27648357
          7fd639b9-5194-4e59-8dfb-4fd2868cce45
          History

          unfolded protein response,colorectal cancer,EZH2,ER stress,Autophagy

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