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Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG.
Anastas, Jamie N; Zee, Barry M; Kalin, Jay H; Kim, Mirhee; Guo, Robyn; Alexandrescu, Sanda; Blanco, Mario Andres; Giera, Stefanie; Gillespie, Shawn M; Das, Jayanta; Wu, Muzhou; Nocco, Sarah; Bonal, Dennis M; Nguyen, Quang-De; Suva, Mario L; Bernstein, Bradley E; Alani, Rhoda; Golub, Todd R; Cole, Philip A; Filbin, Mariella G; Shi, Yang.
Afiliação
  • 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.
Cancer Cell ; 36(5): 528-544.e10, 2019 11 11.
Article em En | MEDLINE | ID: mdl-31631026
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias do Tronco Encefálico / Histona Desmetilases / Inibidores de Histona Desacetilases / Glioma / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias do Tronco Encefálico / Histona Desmetilases / Inibidores de Histona Desacetilases / Glioma / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article