| Literature DB >> 35422502 |
Brian J Golbourn1,2, Matthew E Halbert1,2, Katharine Halligan1,3, Srinidhi Varadharajan4, Brian Krug5,6, Nneka E Mbah7, Nisha Kabir5,8, Ann-Catherine J Stanton1,2, Abigail L Locke1, Stephanie M Casillo1,2, Yanhua Zhao4, Lauren M Sanders9, Allison Cheney9,10, Steven J Mullett11, Apeng Chen1,2,12, Michelle Wassell1,2, Anthony Andren7, Jennifer Perez1,2, Esther P Jane1,2, Daniel R David Premkumar1,2, Robert F Koncar1,2, Shideh Mirhadi13, Lauren H McCarl1,2, Yue-Fang Chang1, Yijen L Wu14, Taylor A Gatesman1,2, Andrea F Cruz1,2, Michal Zapotocky15, Baoli Hu1,2, Gary Kohanbash1,2, Xiuxing Wang16, Alenoush Vartanian17, Michael F Moran13, Frank Lieberman18, Nduka M Amankulor1, Stacy G Wendell11, Olena M Vaske9,10, Ashok Panigrahy19, James Felker20, Kelsey C Bertrand21, Claudia L Kleinman5,8, Jeremy N Rich1, Robert M Friedlander1, Alberto Broniscer2,3, Costas Lyssiotis7, Nada Jabado5,6, Ian F Pollack1,2, Stephen C Mack22,23, Sameer Agnihotri24,25,26.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2022 PMID： 35422502 PMCID： PMC9551679 DOI： 10.1038/s43018-022-00348-3
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347