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 7

Translational relevance of raised l-2HG in RCC.

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Translational relevance of raised l-2HG in RCC. (A) LC-MS analysis of l-...
(A) LC-MS analysis of l-2HG content (normalized to total protein content) from patient tissues harvested from normal kidneys (black dots), high–l-2HG tumors (red dots), or low–l-2HG tumors (blue dots). Data are presented as mean ± SEM from n = 9 samples. Data were analyzed by 1-way ANOVA followed by post hoc Tukey’s honestly significant difference test. ANOVA P value < 0.0001 (F = 18.54). Post hoc analysis P values are shown. (B and C) mRNA expression of PHGDH (B) and PSAT1 (C) from the samples in A. Data are presented as mean ± SEM. Data were analyzed by 1 way ANOVA followed by post hoc Tukey’s honestly significant difference test. ANOVA P values for B and C are 0.0002 (F = 12.91) and 0.0932 (F = 2.624), respectively. Post hoc analysis P values are shown. (D) Immunoblot analysis of PHGDH and PSAT1 from patient-matched (n = 3) high–l-2HG tumors and adjacent normal kidney. The Western blot in the third PHGDH panel is the same blot with shorter exposure time. (E) Relative tumor size of OS-RC-2 xenografts (with or without L2HGDH) at 4 weeks in mice fed chow with or without SerGly. After average tumor size reached 100 mm3, mice were randomly distributed into 2 groups (n = 8 per group). Data are shown as mean ± SEM. (F and G) Immunoblot of L2HGDH protein (F) and densitometric quantification (G) in renal cortical tissue from WT and global-L2HGDH-KO mice. Data were normalized to actin. Data in G are presented as mean ± SEM. (H and I) PHGDH immunoblot and quantification from WT and L2HGDH-KO mouse renal cortical tissues. Data were normalized to actin. Data in I are presented as mean ± SEM. (J) Gas chromatography-MS analysis of serine from WT and global-L2HGDH-KO renal cortical tissues. Data are presented as mean ± SEM from n = 7 mice in each group.