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

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

Free article

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

Jamie N Anastas et al. Cancer Cell. 2019.

Free article

. 2019 Nov 11;36(5):528-544.e10.

doi: 10.1016/j.ccell.2019.09.005. Epub 2019 Oct 17.

Authors

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.

PubMed Disclaimer

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
- Elsevier Science
Other Literature Sources
- The Lens - Patent Citations Database
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Research Materials
- Addgene Non-profit plasmid repository
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials

Miscellaneous