Biochemical and epigenetic insights into L-2-hydroxyglutarate, a potential therapeutic target in renal cancer

Sandeep Shelar, Eun Hee Shim, Garrett J. Brinkley, Anirban Kundu, Francesca Carobbio, Tyler Poston, Jubilee Tan, Vishwas Parekh, Daniel Benson, David K. Crossman, Phillip J. Buckhaults, Dinesh Rakheja, Richard Kirkman, Yusuke Sato, Seishi Ogawa, Shilpa Dutta, Sadanandan E. Velu, Ethan Emberley, Alison Pan, Jason ChenTony Huang, Devin Absher, Anja Becker, Conrad Kunick, Sunil Sudarshan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Purpose: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. Experimental Design: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. Results: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG–dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. Conclusions: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG–driven kidney cancers.

Original languageEnglish (US)
Pages (from-to)6433-6446
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shelar, S., Shim, E. H., Brinkley, G. J., Kundu, A., Carobbio, F., Poston, T., Tan, J., Parekh, V., Benson, D., Crossman, D. K., Buckhaults, P. J., Rakheja, D., Kirkman, R., Sato, Y., Ogawa, S., Dutta, S., Velu, S. E., Emberley, E., Pan, A., ... Sudarshan, S. (2018). Biochemical and epigenetic insights into L-2-hydroxyglutarate, a potential therapeutic target in renal cancer. Clinical Cancer Research, 24(24), 6433-6446. https://doi.org/10.1158/1078-0432.CCR-18-1727