1. Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG
- Author
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Shawn M. Gillespie, Mariella G. Filbin, Mirhee Kim, Sanda Alexandrescu, Rhoda M. Alani, Muzhou Wu, Barry M. Zee, Bradley E. Bernstein, Jayanta Das, Jay H. Kalin, Dennis M. Bonal, Mario Andres Blanco, Yang Shi, Jamie N. Anastas, Mario L. Suvà, Philip A. Cole, Sarah E. Nocco, Stefanie Giera, Quang-Dé Nguyen, Todd R. Golub, and Robyn Guo
- Subjects
0301 basic medicine ,Cancer Research ,animal structures ,Cellular differentiation ,Antineoplastic Agents ,Histone Deacetylases ,Epigenesis, Genetic ,Histones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Pons ,Animals ,Brain Stem Neoplasms ,Humans ,RNA-Seq ,Epigenetics ,Histone Demethylases ,biology ,Chemistry ,Cell Differentiation ,KDM1A ,Glioma ,Cell Biology ,DNA Methylation ,Xenograft Model Antitumor Assays ,Pediatric cancer ,Chromatin ,Gene Expression Regulation, Neoplastic ,Histone Code ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Histone ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,biology.protein ,Demethylase ,Female ,Histone deacetylase - Abstract
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.
- Published
- 2020