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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 Article has an altmetric score of 6

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

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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 1

High l-2HG suppresses amino acid synthesis and transporter genes in RCC.

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High l-2HG suppresses amino acid synthesis and transporter genes in RCC....
(A) Differentially expressed transcripts in RXF-393 control vector (high l-2HG) relative to cells transduced with L2HGDH cDNA (low l-2HG). Amino acid synthesis and transporter genes are indicated (horizontal dashed line denotes P value of 0.05). (B) Relative mRNA of PHGDH and PSAT1 (normalized to RPLPO) from RXF-393 cells stably expressing control black vector or L2HGDH (red). Data are shown as mean ± SD from n = 4 biological replicates. (C and D) Relative mRNA levels of amino acid synthetic/transporter genes from 769p (C) and 786-O (D) cells stably expressing the indicated construct. Expression was normalized to RPLPO. Data are shown as mean ± SD from n = 4 biological replicates. *P < 0.05, **P < 0.005, ***P < 0.0001. (E) Immunoblot of PHGDH, PSAT1, and L2HGDH protein from 769p and 786-O cells transduced with control vector or L2HGDH cDNA. Actin (β-actin) or Ponceau S stain was used as loading control. Blots are from the same biological sample run contemporaneously. (F) Immunoblot of ASNS protein from 786-O and OS-RC-2 RCC cells transduced with control vector or L2HGDH cDNA. Actin was used as loading control. (G and H) Immunoblot of RXF-393 (G) and 769p (H) cells stably expressing control vector, L2HGDH (WT), or L2HGDH A241G (catalytic mutant). Actin was used as loading control. (I) Tandem MS analysis for l-2HG and D-2HG metabolites from control (black) or L2HGDH-KO (red) HK-2 renal epithelial cells normalized to protein content. Data are shown as mean ± SEM from n = 3 biological replicates. (J) mRNA expression of the indicated genes was examined by RT-qPCR from control (black) or L2H DH-KO (red) HK-2 cells. Data are expressed as mean ± SEM from n = 3 biological replicates. *P < 0.05, **P < 0.005. (K) Immunoblot for PHGDH protein from HK-2 cells treated with either DMSO or l-2HG octyl ester (5 mM) or DMOG (1 mM) for 4 hours. Actin was used as loading control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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