Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome
- Nat Cancer. 2022 May;3(5):629-648. doi: 10.1038/s43018-022-00348-3.
- 1. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- 2. John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- 3. Pediatrics, Division of Hematology-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- 4. Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA.
- 5. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
- 6. Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
- 7. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.
- 8. Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada.
- 9. Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, USA.
- 10. University of California Santa Cruz Genomics Institute, Santa Cruz, CA, USA.
- 11. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
- 12. State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, PR China.
- 13. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
- 14. Department of Developmental Biology, University of Pittsburgh and Rangos Research Center Animal Imaging Core, Pittsburgh, PA, USA.
- 15. Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
- 16. Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
- 17. Department of Pharmacy, UPMC Shadyside, Pittsburgh, PA, USA.
- 18. Department of Neurology, Adult Neurooncology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
- 19. Department of Radiology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- 20. Pediatric Neuro-Oncology Program, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
- 21. Department of Pediatric Hematology and Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
- 22. Baylor College of Medicine, Texas Children's Cancer and Hematology Centers, Dan L. Duncan Cancer Center, Houston, TX, USA. [email protected].
- 23. Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. [email protected].
- 24. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
- 25. John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. [email protected].
- 26. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
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.