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 5

High l-2HG causes exogenous serine dependency in RCC cell lines.

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High l-2HG causes exogenous serine dependency in RCC cell lines. (A) LC-...
(A) LC-MS analysis of serine synthesis (m+3) from labeled glucose (U-13C). n = 6 biological replicates. (B) Proliferation of OS-RC-2 cells stably transduced with the indicated vector (left, control; right, L2HGDH) in media with or without SerGly. n = 3 biological replicates. Repeated-measures analysis was conducted, and P values reflect Tukey’s post hoc comparisons. (C and D) Relative growth ratio (–SerGly/+SerGly) at day 4 in RCC cells transduced with the indicated vector. n = 3 biological replicates. *P < 0.05. (E) Immunoblot of PHGDH from 769p cells stably expressing control vector or PHGDH cDNA. (F and G) Proliferation of 769p cells transduced with control vector (F) or PHGDH (G) in media with or without SerGly. n = 3 biological replicates of each group. Repeated-measures analysis was conducted, and P values reflect Tukey’s post hoc comparisons. (H) Immunoblot of Sn12pm6 cells stably expressing the indicated shRNA. (I) Relative l/d-2HG levels in Sn12pm6 cells transduced with the indicated shRNAs (shC, control). n = 3 biological replicates. (J and K) Cell proliferation (by connectivity index) was measured from Sn12pm6-Scr (J) and Sn12pm6-shL2HGDH (K) cells grown with or without SerGly. n = 4 biological replicates of each group. Repeated-measures analysis was conducted, and P values reflect Tukey’s post hoc comparisons. (L) Left: After subcutaneous implantation of OS-RC-2 cells, mice were randomly distributed and fed chow with or without SerGly (n = 10 per group) for 4 weeks. Right: Tumor volume at day 28. Repeated-measures analysis was performed followed by Tukey’s post hoc comparisons at each time point. (M) 786-O xenografts were established in flanks of nude mice. Left: After the average tumor size reached 100 mm3, mice were fed chow with or without SerGly (n = 7 per group) and followed over time (left). Right: Xenograft size (day 40). Repeated-measures analysis was performed followed by Tukey’s post hoc comparisons at each time point Data are shown as (A–D, F, G, J, and K) mean ± SD and (I, L, and M) mean ± SEM.