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

  • Cancer Cell. 2019 Nov 11;36(5):528-544.e10. doi: 10.1016/j.ccell.2019.09.005.
Jamie N Anastas  1 ,  Barry M Zee  1 ,  Jay H Kalin  2 ,  Mirhee Kim  3 ,  Robyn Guo  4 ,  Sanda Alexandrescu  5 ,  Mario Andres Blanco  6 ,  Stefanie Giera  7 ,  Shawn M Gillespie  8 ,  Jayanta Das  9 ,  Muzhou Wu  10 ,  Sarah Nocco  10 ,  Dennis M Bonal  11 ,  Quang-De Nguyen  11 ,  Mario L Suva  12 ,  Bradley E Bernstein  12 ,  Rhoda Alani  10 ,  Todd R Golub  13 ,  Philip A Cole  2 ,  Mariella G Filbin  14 ,  Yang Shi  15
Affiliations
  • 1. 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.
  • 2. 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.
  • 3. NYU Medical School, New York, NY 10016, USA.
  • 4. Duke University, Durham, NC 27708, USA.
  • 5. 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.
  • 6. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7. Sanofi, Cambridge, MA 02139, USA.
  • 8. Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 9. Eshelman School of Pharmacy, UNC Chapel Hill, Chapel Hill, NC 27599, USA.
  • 10. Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
  • 11. Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 12. 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.
  • 13. 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.
  • 14. 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: [email protected].
  • 15. 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: [email protected].
PMID: 31631026 DOI: 10.1016/j.ccell.2019.09.005
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.

Keywords
CRISPR screen; DIPG; HDAC; Histone H3 K27M; LSD1; cancer stem cell; differentiation therapy; enhancer; epigenetic; glioma.
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