Your browser doesn't support javascript.
loading
Histone deacetylase 6 acts upstream of DNA damage response activation to support the survival of glioblastoma cells.
Yang, Wen-Bin; Wu, An-Chih; Hsu, Tsung-I; Liou, Jing-Ping; Lo, Wei-Lun; Chang, Kwang-Yu; Chen, Pin-Yuan; Kikkawa, Ushio; Yang, Shung-Tai; Kao, Tzu-Jen; Chen, Ruei-Ming; Chang, Wen-Chang; Ko, Chiung-Yuan; Chuang, Jian-Ying.
Affiliation
  • Yang WB; TMU Research Center of Neuroscience, Taipei Medical University, 11031, Taipei, Taiwan.
  • Wu AC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 11031, Taipei, Taiwan.
  • Hsu TI; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, 11031, Taipei, Taiwan.
  • Liou JP; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 11031, Taipei, Taiwan.
  • Lo WL; TMU Research Center of Neuroscience, Taipei Medical University, 11031, Taipei, Taiwan.
  • Chang KY; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, 11031, Taipei, Taiwan.
  • Chen PY; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, 11031, Taipei, Taiwan.
  • Kikkawa U; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, 11031, Taipei, Taiwan.
  • Yang ST; School of Pharmacy, College of Pharmacy, Taipei Medical University, 11031, Taipei, Taiwan.
  • Kao TJ; TMU Research Center of Drug Discovery, Taipei Medical University, 11031, Taipei, Taiwan.
  • Chen RM; Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, 23561, New Taipei City, Taiwan.
  • Chang WC; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, 11031, Taipei, Taiwan.
  • Ko CY; National Institute of Cancer Research, National Health Research Institutes, 70456, Tainan, Taiwan.
  • Chuang JY; Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, 20401, Keelung, Taiwan.
Cell Death Dis ; 12(10): 884, 2021 09 28.
Article in En | MEDLINE | ID: mdl-34584069
DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment resistance. Herein, transcriptomic analysis of 177 well-defined DDR genes was performed with normal and GBM specimens (n = 137) from The Cancer Genome Atlas and further integrated with the expression profiling of histone deacetylase 6 (HDAC6) inhibition in temozolomide (TMZ)-resistant GBM cells and patient-derived tumor cells. The effects of HDAC6 inhibition on DDR signaling were examined both in vitro and intracranial mouse models. We found that the expression of DDR genes, involved in repair pathways for DNA double-strand breaks, was upregulated in highly malignant primary and recurrent brain tumors, and their expression was related to abnormal clinical features. However, a potent HDAC6 inhibitor, MPT0B291, attenuated the expression of these genes, including RAD51 and CHEK1, and was more effective in blocking homologous recombination repair in GBM cells. Interestingly, it resulted in lower cytotoxicity in primary glial cells than other HDAC6 inhibitors. MPT0B291 reduced the growth of both TMZ-sensitive and TMZ-resistant tumor cells and prolonged survival in mouse models of GBM. We verified that HDAC6 regulated DDR genes by affecting Sp1 expression, which abolished MPT0B291-induced DNA damage. Our findings uncover a regulatory network among HDAC6, Sp1, and DDR genes for drug resistance and survival of GBM cells. Furthermore, MPT0B291 may serve as a potential lead compound for GBM therapy.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Damage / Glioblastoma / Histone Deacetylase 6 Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Cell Death Dis Year: 2021 Document type: Article Affiliation country: Taiwan Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Damage / Glioblastoma / Histone Deacetylase 6 Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Cell Death Dis Year: 2021 Document type: Article Affiliation country: Taiwan Country of publication: United kingdom