Journal article
Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG
- 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 status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
-
-
(Preview, Accepted manuscript, pdf, 8.6MB, Terms of use)
-
- Publisher copy:
- 10.1016/j.ccell.2019.09.005
Authors
- Publisher:
- Cell Press
- Journal:
- Cancer Cell More from this journal
- Volume:
- 36
- Issue:
- 5
- Pages:
- 528-544.e10
- Publication date:
- 2019-10-17
- Acceptance date:
- 2019-09-12
- DOI:
- EISSN:
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1878-3686
- ISSN:
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1535-6108
- Language:
-
English
- Keywords:
- Pubs id:
-
1113262
- Local pid:
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pubs:1113262
- Deposit date:
-
2020-08-10
- ARK identifier:
Terms of use
- Copyright holder:
- Elsevier Inc.
- Copyright date:
- 2019
- Rights statement:
- © 2019 Elsevier Inc.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from Cell Press at: https://doi.org/10.1016/j.ccell.2019.09.005
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