Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.

Autor:	Anastas JN; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Zee BM; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Kalin JH; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Womens Hospital, Boston, MA 02115, USA., Kim M; NYU Medical School, New York, NY 10016, USA., Guo R; Duke University, Durham, NC 27708, USA., Alexandrescu S; Department of Pathology Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA., Blanco MA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Giera S; Sanofi, Cambridge, MA 02139, USA., Gillespie SM; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA., Das J; Eshelman School of Pharmacy, UNC Chapel Hill, Chapel Hill, NC 27599, USA., Wu M; Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA., Nocco S; Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA., Bonal DM; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Suva ML; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Bernstein BE; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA., Alani R; Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA., Golub TR; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, 20815 MD, USA., Cole PA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Womens Hospital, Boston, MA 02115, USA., Filbin MG; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: mariella.filbin@childrens.harvard.edu., Shi Y; Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: yang_shi@hms.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2019 Nov 11; Vol. 36 (5), pp. 528-544.e10. Date of Electronic Publication: 2019 Oct 17.
DOI:	10.1016/j.ccell.2019.09.005
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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