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L-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models
- Source :
- Journal of Clinical Investigation. July 2024, Vol. 134 Issue 13
- Publication Year :
- 2024
-
Abstract
- Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule l-2-hydroxyglutarate (L-2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, L-2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L-2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA [N.sup.6]- methyladenosine. The combined effects of L-2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high-L-2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high-L-2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.<br />Introduction Oncometabolites are small molecules that aberrantly accumulate within tumor cells. These small molecules can have either tumor-promoting or -suppressive effects, indicating that their impact on tumor biology is highly [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 134
- Issue :
- 13
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.803497471
- Full Text :
- https://doi.org/10.1172/JCI171294