Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma
Open accessAbstract
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.
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DNMT inhibitors have broad cellular effects due to indiscriminate inhibition of all DNMT-containing complexes, leading to a global loss of DNA methylation.
“These inhibitors therefore have broad cellular effects due to indiscriminate inhibition of all DNMT-containing complexes, leading to a global loss of DNA methylation 121 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [121]
In SF8628 DIPG cells, the genome-wide distribution of H3.3K27M is highly correlated with active transcription, as shown by co-localization with H3K27ac and RNA polymerase II.
“ChIP-seq results from SF8628 human DIPG cells, containing a mutant H3F3A gene encoding H3.3K27M8, reveal a genome wide distribution of H3.3K27M that is highly correlated with active transcription, as indicated by the co-localization of acetylated H3K27 (H3K27ac) and RNA polymerase II (RNA pol II) (Fig. 1A–C and Supplementary Fig. 2A–B).”
From Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas (2017) · cites this paper as [8]
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References 21 · Cited by 476
- Authors
- Hashizume, R., Andor, N., Ihara, Y., Lerner, R., Gan, H., Chen, X., Fang, D., Huang, X., Tom, M. W., Ngo, V., Solomon, D., Mueller, S., Paris, P. L., Zhang, Z., Petritsch, C., Gupta, N., Waldman, T. A., & James, C. D.
- Affiliations
- Northwestern University (US)
- University of California, San Francisco (US)
- Mayo Clinic (US)
- Georgetown University (US)
- Corresponding author
- Hashizume, Rintaro
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-11-17
- Volume
- 20
- Issue
- 12
- Pages
- 1394-1396
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4257862
- OpenAlex
- W2022930470
- Cited by
- 476
- References
- 21
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 34 · 2023: 36 · 2022: 38 · 2021: 43 · 2020: 62 · 2019: 48 · 2018: 53 · 2017: 61 · 2016: 46 · 2015: 23 · 2014: 5
- FWCI
- 22.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CLOK (University of Central Lancashire) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA157489, R01CA159467, CA157489, R01CA164746, CA97257, CA164746, P50CA097257)
- National Institute of Neurological Disorders and Stroke (R01NS080619)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- pediatric brainstem glioma, JMJD3, H3K27 demethylase, H3K27 methylation, H3F3A mutation, cancer therapy, xenografts
- MeSH terms
- Animals, Benzazepines, Child, Glioma, Histones, Humans, Methylation, Pyrimidines, Gene Expression Regulation, Neoplastic, Apoptosis, Brain Stem Neoplasms, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Jumonji Domain-Containing Histone Demethylases
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