Targeting Glioma Stem-Like Cell Survival and Chemoresistance Through Inhibition of Lysine-Specific Histone Demethylase KDM2B

Mol Oncol. 2018 Mar;12(3):406-420. doi: 10.1002/1878-0261.12174. Epub 2018 Feb 12.

Abstract

Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter- and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem-like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient-derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.

Keywords: cancer stem-like cell; chemoresistance; epigenetics; glioblastoma; histone demethylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Apoptosis / drug effects
  • Astrocytes / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Line
  • DNA Damage / drug effects
  • Drug Resistance, Neoplasm*
  • Etoposide / administration & dosage
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lomustine / administration & dosage
  • Lysine / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Primary Cell Culture

Substances

  • Antineoplastic Agents
  • F-Box Proteins
  • Histones
  • Etoposide
  • Lomustine
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • Lysine