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

Jamie N Anastas; Barry M Zee; Jay H Kalin; Mirhee Kim; Robyn Guo; Sanda Alexandrescu; Mario Andres Blanco; Stefanie Giera; Shawn M Gillespie; Jayanta Das; Muzhou Wu; Sarah Nocco; Dennis M Bonal; Quang-De Nguyen; Mario L Suva; Bradley E Bernstein; Rhoda Alani; Todd R Golub; Philip A Cole; Mariella G Filbin; Yang Shi

doi:10.1016/j.ccell.2019.09.005

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. Epub 2019 Oct 17.

Authors

Jamie N Anastas¹, Barry M Zee¹, Jay H Kalin², Mirhee Kim³, Robyn Guo⁴, Sanda Alexandrescu⁵, Mario Andres Blanco⁶, Stefanie Giera⁷, Shawn M Gillespie⁸, Jayanta Das⁹, Muzhou Wu¹⁰, Sarah Nocco¹⁰, Dennis M Bonal¹¹, Quang-De Nguyen¹¹, Mario L Suva¹², Bradley E Bernstein¹², Rhoda Alani¹⁰, Todd R Golub¹³, Philip A Cole², Mariella G Filbin¹⁴, Yang Shi¹⁵

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: mariella.filbin@childrens.harvard.edu.
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: yang_shi@hms.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Brain Stem Neoplasms / drug therapy*
Brain Stem Neoplasms / genetics
Brain Stem Neoplasms / mortality
Brain Stem Neoplasms / pathology
Cell Differentiation / drug effects
Cell Differentiation / genetics
Cell Line, Tumor
Chromatin / metabolism
DNA Methylation / drug effects
DNA Methylation / genetics
Epigenesis, Genetic / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Glioma / drug therapy*
Glioma / genetics
Glioma / mortality
Glioma / pathology
Histone Code / drug effects
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylase Inhibitors / therapeutic use
Histone Deacetylases / metabolism
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / genetics
Histone Demethylases / metabolism
Histones / metabolism
Humans
Mice
Mutation
Pons / pathology
RNA-Seq
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Chromatin
Histone Deacetylase Inhibitors
Histones
Histone Demethylases
KDM1A protein, human
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding