Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG
| Autor: | 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, Robyn Guo |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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