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

Anticancer Res. 2019 Dec;39(12):6731-6741. doi: 10.21873/anticanres.13888.


Background/aim: 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.

Materials and methods: 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.

Results: 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.

Conclusion: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.

Keywords: DNA mismatch repair; Histone deacetylase 6; MutSα; glioblastoma; temozolomide resistance.

MeSH terms

  • Antineoplastic Agents, Alkylating / therapeutic use
  • Benzene Derivatives / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / enzymology*
  • Cell Line, Tumor
  • Cell Survival
  • DNA Mismatch Repair / physiology
  • DNA Modification Methylases / metabolism
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / metabolism
  • Glioblastoma / drug therapy
  • Glioblastoma / enzymology*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles / pharmacology
  • MutS Homolog 2 Protein / metabolism*
  • Pyrimidines / pharmacology
  • Temozolomide / therapeutic use
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation


  • A452 compound
  • Antineoplastic Agents, Alkylating
  • Benzene Derivatives
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Pyrimidines
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • tubastatin A
  • DNA Modification Methylases
  • MGMT protein, human
  • EGFR protein, human
  • ErbB Receptors
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • MSH2 protein, human
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes
  • ricolinostat
  • Temozolomide