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l -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer
Open accessPublished version of a preprint
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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“Furthermore, increased L-2-HG levels caused by reduced expression of L2HGDH have been reported in renal cancer96.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [96]
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“In addition, a specific increase in the L enantiomer of 2-HG, which was shown to exert similar, but not identical, inhibitory effects on α-ketoglutarate-dependent dioxygenases was found in clear cell renal cell carcinoma, where it correlates with increased methylcytosine levels (Shim et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Shim et al., 2014
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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression
Sreekumar, A., Poisson, L., Rajendiran, T. M., Khan, A. P., Cao, Q., Yu, J., Laxman, B., Mehra, R., Lonigro, R. J., Li, Y., et al. (2009) · Nature · doi:10.1038/nature07762 · Cited by 2,269
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791
Mutation in TET2 in Myeloid Cancers
Delhommeau, F., Dupont, S., Valle, V. D., James, C., Trannoy, S., Massé, A., Kosmider, O., Le Couedic, J.-P., Robert, F., Alberdi, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810069 · Cited by 1,776
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2
Ko, M., Huang, Y., Jankowska, A. M., Pape, U. J., Tahiliani, M., Bandukwala, H. S., An, J., Lamperti, E. D., Koh, K. P., Ganetzky, R. D., et al. (2010) · Nature · doi:10.1038/nature09586 · Cited by 1,340
Integrated molecular analysis of clear-cell renal cell carcinoma
Sato, Y., Yoshizato, T., Shiraishi, Y., Maekawa, S., Okuno, Y., Kamura, T., Shimamura, T., Sato‐Otsubo, A., Nagae, G., Suzuki, H., et al. (2013) · Nature Genetics · doi:10.1038/ng.2699 · Cited by 1,257
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DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
Mitochondrial TCA cycle metabolites control physiology and disease
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Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
Cancer metabolism: looking forward
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Metadata
- 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
- Venue
- Cancer Discovery
- Published
- 2014-11-01
- Volume
- 4
- Issue
- 11
- Pages
- 1290-1298
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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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