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DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma.
Zhang, Lian; Li, Hong-Tao; Shereda, Rachel; Lu, Qianjin; Weisenberger, Daniel J; O'Connell, Casey; Machida, Keigo; An, Woojin; Lenz, Heinz-Josef; El-Khoueiry, Anthony; Jones, Peter A; Liu, Minmin; Liang, Gangning.
Afiliação
  • Zhang L; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA; Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • Li HT; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
  • Shereda R; Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
  • Lu Q; Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • Weisenberger DJ; Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • O'Connell C; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
  • Machida K; Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
  • An W; Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • Lenz HJ; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
  • El-Khoueiry A; Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA.
  • Jones PA; Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
  • Liu M; Van Andel Research Institute, Grand Rapids, MI, 49503, USA. Electronic address: Minmin.Liu@vai.org.
  • Liang G; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90089, USA. Electronic address: gliang@usc.edu.
Cancer Lett ; 548: 215899, 2022 11 01.
Article em En | MEDLINE | ID: mdl-36087682
ABSTRACT
The development of more effective targeted therapies for hepatocellular carcinoma (HCC) patients due to its aggressiveness is urgently needed. DNA methyltransferase inhibitors (DNMTis) represented the first clinical breakthrough to target aberrant cancer epigenomes. However, their clinical efficacies are still limited, in part due to an "epigenetic switch" in which a large group of genes that are demethylated by DNMTi treatment remain silenced by polycomb repressive complex 2 (PRC2) occupancy. EZH2 is the member of PRC2 that catalyzes the placement of H3K27me3 marks. EZH2 overexpression is correlated with poor HCC patient survival. We tested the combination of a DNMTi (5-aza-2'-deoxycytidine, DAC) and the EZH2 inhibitor (EZH2i) GSK126 in human HCC cell lines on drug sensitivity, DNA methylation, nucleosome accessibility, and gene expression profiles. Compared with single agent treatments, all HCC cell lines studied showed increased sensitivity after receiving both drugs concomitant with prolonged anti-proliferative changes and sustained reactivation of nascently-silenced genes. The increased number of up-regulated genes after combination treatment correlated with prolonged anti-proliferation effects and increased nucleosome accessibility. Combination treatments also activate demethylated promoters that are repressed by PRC2 occupancy. Furthermore, 13-31% of genes down-regulated by DNA methylation in primary HCC tumors were reactivated through this combination treatment scheme in vitro. Finally, the combination treatment also exacerbates anti-tumor immune responses, while most of these genes were downregulated in over 50% of primary HCC tumors. We have linked the anti-tumor effects of DAC and GSK126 combination treatments to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets and provided a rationale for treatment efficacy for HCC patients.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / DNA (Citosina-5-)-Metiltransferases / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: Cancer Lett Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / DNA (Citosina-5-)-Metiltransferases / Neoplasias Hepáticas Limite: Humans Idioma: En Revista: Cancer Lett Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China
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