Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Rintaro Hashizume; Noemi Andor; Yuichiro Ihara; Robin Lerner; Haiyun Gan; Xiaoyue Chen; Dong Fang; Xi Huang; Maxwell W Tom; Vy Ngo; David Solomon; Sabine Mueller; Pamela L Paris; Zhiguo Zhang; Claudia Petritsch; Nalin Gupta; Todd A Waldman; C David James

doi:10.1038/nm.3716

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

Nat Med. 2014 Dec;20(12):1394-6. doi: 10.1038/nm.3716. Epub 2014 Nov 17.

Authors

Rintaro Hashizume¹, Noemi Andor², Yuichiro Ihara², Robin Lerner², Haiyun Gan³, Xiaoyue Chen³, Dong Fang³, Xi Huang⁴, Maxwell W Tom², Vy Ngo⁵, David Solomon⁶, Sabine Mueller⁷, Pamela L Paris⁵, Zhiguo Zhang³, Claudia Petritsch², Nalin Gupta², Todd A Waldman⁸, C David James¹

Affiliations

¹ Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
² Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
³ Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Department of Physiology, University of California, San Francisco, San Francisco, California, USA.
⁵ Department of Urology, University of California, San Francisco, San Francisco, California, USA.
⁶ 1] Department of Pathology, University of California, San Francisco, San Francisco, California, USA. [2] Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
⁷ 1] Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, San Francisco, California, USA. [3] Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
⁸ Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.

PMID: 25401693
PMCID: PMC4257862
DOI: 10.1038/nm.3716

Abstract

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Publication types

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

MeSH terms

Animals
Apoptosis / drug effects*
Benzazepines / pharmacology*
Brain Stem Neoplasms / genetics*
Brain Stem Neoplasms / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects*
Child
Gene Expression Regulation, Neoplastic*
Glioma / genetics*
Glioma / metabolism
Histones / drug effects*
Histones / genetics
Histones / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
Jumonji Domain-Containing Histone Demethylases / metabolism
Methylation / drug effects
Mice
Pyrimidines / pharmacology*
Xenograft Model Antitumor Assays

Substances

Benzazepines
GSK-J4
Histones
Pyrimidines
Jumonji Domain-Containing Histone Demethylases
KDM6B protein, human

Associated data

GEO/GSE59497

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding