Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG. Academic Article uri icon

Overview

abstract

  • H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs.

publication date

  • October 17, 2019

Research

keywords

  • Antineoplastic Agents
  • Brain Stem Neoplasms
  • Glioma
  • Histone Deacetylase Inhibitors
  • Histone Demethylases

Identity

Scopus Document Identifier

  • 85074387823

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2019.09.005

PubMed ID

  • 31631026

Additional Document Info

volume

  • 36

issue

  • 5