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Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome
BJ. Golbourn, ME. Halbert, K. Halligan, S. Varadharajan, B. Krug, NE. Mbah, N. Kabir, AJ. Stanton, AL. Locke, SM. Casillo, Y. Zhao, LM. Sanders, A. Cheney, SJ. Mullett, A. Chen, M. Wassell, A. Andren, J. Perez, EP. Jane, DRD. Premkumar, RF....
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
Grant support
R01 NS116361
NINDS NIH HHS - United States
R01 NS115831
NINDS NIH HHS - United States
T32 GM133391
NIGMS NIH HHS - United States
S10 OD023402
NIH HHS - United States
PJT-156086
CIHR - Canada
- MeSH
- Epigenome MeSH
- Glioma * genetics MeSH
- Histones genetics MeSH
- Methionine genetics MeSH
- Methionine Adenosyltransferase metabolism MeSH
- Mice MeSH
- Brain Neoplasms * genetics MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.
Department of Cell Biology School of Basic Medical Sciences Nanjing Medical University Nanjing China
Department of Developmental Neurobiology St Jude Children's Research Hospital Memphis TN USA
Department of Human Genetics McGill University Montreal Quebec Canada
Department of Molecular Cell and Developmental Biology University of California Santa Cruz CA USA
Department of Molecular Genetics University of Toronto Toronto Ontario Canada
Department of Neurobiology University of Pittsburgh Pittsburgh PA USA
Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh PA USA
Department of Neurology Adult Neurooncology Program UPMC Hillman Cancer Center Pittsburgh PA USA
Department of Pediatric Hematology and Oncology St Jude Children's Research Hospital Memphis TN USA
Department of Pharmacology and Chemical Biology University of Pittsburgh Pittsburgh PA USA
Department of Pharmacy UPMC Shadyside Pittsburgh PA USA
Department of Radiology Children's Hospital of Pittsburgh Pittsburgh PA USA
John G Rangos Sr Research Center Children's Hospital of Pittsburgh Pittsburgh PA USA
Lady Davis Research Institute Jewish General Hospital Montreal Quebec Canada
Pediatric Neuro Oncology Program UPMC Children's Hospital of Pittsburgh Pittsburgh PA USA
University of California Santa Cruz Genomics Institute Santa Cruz CA USA
References provided by Crossref.org
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