l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models
Anirban Kundu, … , Jason M. Tennessen, Sunil Sudarshan
Anirban Kundu, … , Jason M. Tennessen, Sunil Sudarshan
Published May 14, 2024
Citation Information: J Clin Invest. 2024;134(13):e171294. https://doi.org/10.1172/JCI171294.
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Research Article Metabolism Oncology

l-2-Hydroxyglutarate remodeling of the epigenome and epitranscriptome creates a metabolic vulnerability in kidney cancer models

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 N6-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.

Authors

Anirban Kundu, Garrett J. Brinkley, Hyeyoung Nam, Suman Karki, Richard Kirkman, Madhuparna Pandit, EunHee Shim, Hayley Widden, Juan Liu, Yasaman Heidarian, Nader H. Mahmoudzadeh, Alexander J. Fitt, Devin Absher, Han-Fei Ding, David K. Crossman, William J. Placzek, Jason W. Locasale, Dinesh Rakheja, Jonathan E. McConathy, Rekha Ramachandran, Sejong Bae, Jason M. Tennessen, Sunil Sudarshan

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Figure 6

Exogenous serine is required for glutathione synthesis in RCC.

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Exogenous serine is required for glutathione synthesis in RCC. (A) Princ...
(A) Principal component plot from partial least-squares discriminant analysis of metabolites from 769p cells grown in media containing both serine and glycine, glycine only, or no serine and glycine (None) (n = 5 biological replicates per group). (B) LC-MS analysis of metabolites extracted from the 3 groups of 769p cells described in A. (C) Schematic view of serine and glycine incorporation into glutathione (GSH). (D) Analysis of cellular GSH levels from 769p cells cultured for 24 hours in media as indicated. Results are presented as mean ± SEM from n = 4 biological replicates of each group. ANOVA P value < 0.0001. Post hoc Tukey’s P values are shown. (E) Analysis of cellular GSH levels from 769p cells cultured for 24 hours in serine-containing media with or without BSO. Data are presented as mean ± SD from n = 3 biological replicates per group. (F) Cell proliferation as determined by connectivity index in 769p cells grown as indicated. Each data point represents mean ± SD from n = 4 biological replicates of each group. (G and H) GSH levels of 786-O (G) and 769p (H) cells stably expressing control vector or L2HGDH and cultured for 24 hours in media with or without (None) serine. Data are shown as mean ± SEM from n = 3 biological replicates in each group. *P < 0.05, **P < 0.005. (I and J) Relative fraction of viable cells in 786-O (I) and 769p (J) cells stably expressing the indicated vector and treated with 100 mM tert-butyl H2O2 for 24 hours in the presence or absence of SerGly. Results are presented as mean ± SEM from n = 3 biological replicates of each group. *P < 0.05, **P < 0.005, ***P < 0.0001. (K) Quantification of GSH content in 786-O xenografts in mice fed chow with or without SerGly. Xenografts are from data presented in Figure 5M. Results are presented as mean ± SEM. *P < 0.05.