title: In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes.
abstract: There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC. In this study, an in silico study was performed and found that EZH2 was overexpressed in cancerous tissues of HCC patients at both gene and protein levels. Microarray analysis and in vitro experiments indicated that the anti-HCC activity of GSK343 was associated with the induction of metallothionein (MT) genes. In addition, the negative association of EZH2 and MT1/MT2A genes in cancer cell lines and tissues was found in public gene expression database. Taken together, our findings suggest that EZH2 inhibitors could be a good therapeutic option for HCC, and induction of MT genes was associated with the anti-HCC activity of EZH2 inhibitors.
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan; Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Tsang-Pai
authors.initials: TP
authors.lastname: Liu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yi-Han
authors.initials: YH
authors.lastname: Hong
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Kwang-Yi
authors.initials: KY
authors.lastname: Tung
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Pei-Ming
authors.initials: PM
authors.lastname: Yang
keywords: EZH2; hepatocellular carcinoma; metallothionein; microarray analysis; therapeutic biomarker