Cancer Cell
Volume 36, Issue 5, 11 November 2019, Pages 528-544.e10
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Article
Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

https://doi.org/10.1016/j.ccell.2019.09.005Get rights and content
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Highlights

  • A CRISPR screen for HDAC inhibitor sensitizers in DIPG identifies KDM1A (LSD1)

  • Corin, a dual inhibitor of LSD1 and HDACs, inhibits DIPG growth in vitro and in vivo

  • Corin alters histone modifications to promote differentiation and block cell cycle

  • A Corin-induced gene expression signature correlates with prolonged survival in DIPG

Summary

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.

Keywords

DIPG
CRISPR screen
Histone H3 K27M
HDAC
LSD1
epigenetic
differentiation therapy
enhancer
glioma
cancer stem cell

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18

These authors contributed equally

19

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