Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.
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.
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Rintaro
R
Hashizume
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Noemi
N
Andor
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Yuichiro
Y
Ihara
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Robin
R
Lerner
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Haiyun
H
Gan
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Xiaoyue
X
Chen
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Dong
D
Fang
Department of Physiology, University of California, San Francisco, San Francisco, California, USA.
Xi
X
Huang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Maxwell W
MW
Tom
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
Vy
V
Ngo
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.
David
D
Solomon
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.
Sabine
S
Mueller
Department of Urology, University of California, San Francisco, San Francisco, California, USA.
Pamela L
PL
Paris
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Zhiguo
Z
Zhang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Claudia
C
Petritsch
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Nalin
N
Gupta
Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
Todd A
TA
Waldman
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
C David
CD
James
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D001552:Benzazepines; C000593030:GSK-J4; D006657:Histones; D011743:Pyrimidines; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human