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.
authors.affiliation: aPhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University bDepartment of Surgery, Mackay Memorial Hospital, Taipei cMackay Junior College of Medicine, Nursing and Management dDepartment of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Tsang-Pai
authors.initials: TP
authors.lastname: Liu
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Lo
authors.forename: Li-Shan
authors.initials: LS
authors.lastname: Wei
authors.forename: Heidi Hao-yun
authors.initials: HH
authors.lastname: Hsiao
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Yang
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells / Q000187:drug effects; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D012436:S-Adenosylmethionine / Q000378:metabolism; D000077157:Sorafenib
chemical_list: D004791:Enzyme Inhibitors; C586265:GSK343; D007191:Indazoles; D010671:Phenylurea Compounds; D011728:Pyridones; D009536:Niacinamide; C048460:3-deazaneplanocin; D012436:S-Adenosylmethionine; D000077157:Sorafenib; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D000241:Adenosine