Cited by 280Cancer, Hypoxia, and MetabolismEpigenetics and DNA MethylationRNA modifications and cancer

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l -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer

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Shim, Eun-Hee, Livi, Carolina B., Rakheja, Dinesh, Tan, Jubilee, Benson, Daniel, Parekh, Vishwas, Kho, Eun-Young, Ghosh, Arindam P., Kirkman, Richard, Velu, Sadanan, Dutta, Shilpa, Chenna, Balachandra, Rea, Shane L., Mishur, Robert J., Li, Qiuhua, Johnson-Pais, Teresa L., Guo, Lining, Bae, Sejong, Wei, Shi, Block, Karen, Sudarshan, Sunil·2014·Cancer Discovery

DOI 10.1158/2159-8290.cd-13-0696PMC PMC4286872

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Abstract

Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)–dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors. In contrast, kidney tumors demonstrate elevations of the l enantiomer of 2HG (l-2HG). High-2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC), consistent with 2HG-mediated inhibition of ten-eleven translocation (TET) enzymes, which convert 5-methylcytosine (5mC) to 5hmC. l-2HG elevation is mediated in part by reduced expression of l-2HG dehydrogenase (L2HGDH). L2HGDH reconstitution in RCC cells lowers l-2HG and promotes 5hmC accumulation. In addition, L2HGDH expression in RCC cells reduces histone methylation and suppresses in vitro tumor phenotypes. Our report identifies l-2HG as an epigenetic modifier and putative oncometabolite in kidney cancer. Significance: Here, we report elevations of the putative oncometabolite l-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer. Cancer Discov; 4(11); 1290–8. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1243

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Additional file 3 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759755
Additional file 4 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759758
Additional file 9 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759773
Additional file 5 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759761
Additional file 11 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759740
Additional file 1 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759749
Additional file 6 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759764
Additional file 12 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759746
Additional file 1 of The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity
Zhang, F., Niu, M., Guo, K., Ma, Y., Fu, Q., Liu, Y., Feng, Z., Mi, W., & Wang, L. (2022) · Figshare · doi:10.6084/m9.figshare.20267414
Additional file 10 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759737
Additional file 2 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759752
Additional file 7 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759767
Additional file 8 of GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma
Fang, Z., Zhang, N., Yuan, X., Xing, X., Li, X., Qin, X., Liu, Z., Neo, S., Liu, C., Kong, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19759770
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Han, X.-X., Pang, K., Sun, J.-H., Lou, Y.-F., Zhang, Z.-Y., Bao, J.-S., Yu, Y., Liu, X., Hou, J., Liu, Y., et al. (2026) · Drug Resistance Updates · doi:10.1016/j.drup.2026.101441
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Hou, T., Hua, X., Wei Min, N. I., Yan, P., Inuzuka, H., & Wei, W. (2026) · Cell Death and Differentiation · doi:10.1038/s41418-026-01857-9
Chiral Analysis of 2-Hydroxyglutarate in IDH-mut Glioma Tissue using the Kinetic Method
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Authors: Shim, E.-H., Livi, C. B., Rakheja, D., Tan, J., Benson, D., Parekh, V., Kho, E.-Y., Ghosh, A. P., Kirkman, R., Velu, S., Dutta, S., Chenna, B., Rea, S. L., Mishur, R. J., Li, Q., Johnson-Pais, T. L., Guo, L., Bae, S., Wei, S., Block, K., & Sudarshan, S.
Affiliations: University of Alabama at Birmingham (US)
The University of Texas at San Antonio Health Science Center (US)
The University of Texas Southwestern Medical Center (US)
5Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama.
7Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.
Metabolon (United States) (US)
Corresponding author: Sudarshan, Sunil
ORCID: Shim, Eun-Hee
Livi, Carolina B.
Rakheja, Dinesh
Parekh, Vishwas
Kirkman, Richard
Dutta, Shilpa
Chenna, Balachandra
Rea, Shane L.
Mishur, Robert J.
Li, Qiuhua
Guo, Lining
Bae, Sejong
Wei, Shi
Sudarshan, Sunil
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2014-11-01
Volume: 4
Issue: 11
Pages: 1290-1298
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-13-0696
PMC: PMC4286872
OpenAlex: W1984882020
Cited by: 280
References: 39
Citations by year: 2026: 12 · 2025: 11 · 2024: 27 · 2023: 17 · 2022: 42 · 2021: 35 · 2020: 23 · 2019: 28 · 2018: 23 · 2017: 25 · 2016: 21 · 2015: 15 · 2014: 1
FWCI: 6.60
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UL1TR001120, KL2TR001118)
University of Texas Health Science Center at San Antonio
National Cancer Institute (P30CA054174, R01CA131272, R01 NCI CA131272, K08CA138774, P30CA013148)
National Center for Research Resources (UL1RR025767)
National Center for Advancing Translational Sciences
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords: L-2-hydroxyglutarate, renal cell carcinoma, oncometabolites, epigenetic regulators, 5-hydroxymethylcytosine, TET enzymes, IDH mutation, 2-oxoglutarate-dependent dioxygenase, histone methylation, DNA demethylation, histone demethylation, cancer metabolism
MeSH terms: Carcinoma, Renal Cell, Glutarates, Humans, Kidney Neoplasms, RNA, Messenger, Epigenesis, Genetic, Cell Line, Tumor, HEK293 Cells

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l -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer

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