Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

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.

• Authors: 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
• Journal: Cell stem cell (Cell Stem Cell) Vol. 20 Issue 2 Pg. 233-246.e7 (02 02 2017) ISSN: 1875-9777 [Electronic] United States
• PMID: 27989769 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Histones
• Nuclear Proteins
• Protein Kinase Inhibitors
• Receptors, Notch
• Histone Demethylases
• Jumonji Domain-Containing Histone Demethylases
• KDM6A protein, human
• KDM6B protein, human
• Protein Kinases
• Lysine

Topics

• Acetylation (drug effects)
• Base Sequence
• Biomarkers, Tumor (metabolism)
• Brain (drug effects, growth & development, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatin Assembly and Disassembly (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Enhancer Elements, Genetic (genetics)
• Glioblastoma (metabolism, pathology)
• Histone Demethylases (metabolism)
• Histones (metabolism)
• Humans
• Jumonji Domain-Containing Histone Demethylases (metabolism)
• Lysine (metabolism)
• Methylation (drug effects)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Nuclear Proteins (metabolism)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)