Journal
CANCER CELL
Volume 36, Issue 5, Pages 528-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.09.005
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Funding
- Cure Starts Now Foundation
- DIPG Collaborative
- National Cancer Institute [R35 CA210104-01]
- Boston Children's Hospital
- Ruth L. Kirchstein Fellowship from the National Cancer Institute [F32 CA189741-01]
- Rally Foundation for Pediatric Cancer Research
- Vs. Cancer
- Defeat DIPG/Mark Mosier Foundation
- Chad Tough Foundation
- Burroughs Wellcome Fund
- NIH [3P30 CA006516-53S6, F32GM108364, R37GM62437]
- Musella Foundation
- DIPG All-In-Initiative
- Solving Kids' Cancer, Inc/The Bibi Fund
- Andruzzi Foundation
- Alex's Lemonade Stand Foundation
- Harvard College
- Harvard Program in Neonatology Summer Student Research Program
- V Foundation
- FAMRI Foundation
- Leukemia and Lymphoma Society
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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.
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