Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance

Brian B. Liau, Cem Sievers, Laura K. Donohue, Shawn M. Gillespie, William A. Flavahan, Tyler E. Miller, Andrew S. Venteicher, Christine H. Hebert, Christopher D. Carey, Scott J. Rodig, Sarah J. Shareef, Fadi J. Najm, Peter van Galen, Hiroaki Wakimoto, Daniel P. Cahill, Jeremy N. Rich, Jon C. Aster, Mario L. Suvà, Anoop P. Patel, Bradley E. Bernstein

Research output: Contribution to journalArticlepeer-review

334 Scopus citations

Abstract

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Original languageEnglish (US)
Pages (from-to)233-246.e7
JournalCell Stem Cell
Volume20
Issue number2
DOIs
StatePublished - Feb 2 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • KDM6A/B
  • Notch
  • cancer
  • chromatin
  • drug resistance
  • epigenetics
  • glioblastoma
  • histone demethylases
  • stem cell

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