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Temozolomide-resistant Glioblastoma Depends on HDAC6 Activity Through Regulation of DNA Mismatch Repair.

Authors
  • Kim, Go Woon1
  • Lee, Dong Hoon1
  • Yeon, Soo-Keun1
  • Jeon, Yu Hyun1
  • Yoo, Jung1
  • Lee, Sang Woo1
  • Kwon, So Hee2, 3
  • 1 College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea. , (North Korea)
  • 2 College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea [email protected] , (North Korea)
  • 3 Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea. , (North Korea)
Type
Published Article
Journal
Anticancer Research
Publisher
International Institute of Anticancer Research
Publication Date
Dec 01, 2019
Volume
39
Issue
12
Pages
6731–6741
Identifiers
DOI: 10.21873/anticanres.13888
PMID: 31810938
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM. Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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