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L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Shim, Eun-Hee Livi, Carolina B. Rakheja, Dinesh Tan, Jubilee Benson, Daniel G. Parekh, Vishwas Kho, Eun-Young Ghosh, Arindam P. Kirkman, Richard L. Velu, Sadanan Dutta, Shilpa Chenna, Balachandra Rea, Shane L. Mishur, Robert J. Li, Qiuhua Johnson-Pais, Teresa L. Guo, Li-Ning Bae, Sejong Block, Karen L. Sudarshan, Sunil H. |
| Copyright Year | 2014 |
| Abstract | UNLABELLED 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/2159-8290.CD-13-0696 |
| PubMed reference number | 25182153 |
| Journal | Medline |
| Volume Number | 4 |
| Issue Number | 11 |
| Alternate Webpage(s) | http://www.pathology.washington.edu/research/labs/rea/asset/publications/7.pdf |
| Alternate Webpage(s) | http://cancerdiscovery.aacrjournals.org/content/candisc/4/11/1290.full.pdf |
| Alternate Webpage(s) | http://cancerdiscovery.aacrjournals.org/content/candisc/early/2014/08/30/2159-8290.CD-13-0696.full.pdf |
| Alternate Webpage(s) | http://vhl.org/wp-content/uploads/2015/11/VHL-Meeting-talk-for-EJ.pdf |
| Alternate Webpage(s) | http://cancerdiscovery.aacrjournals.org/content/candisc/early/2014/10/08/2159-8290.CD-13-0696.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/2159-8290.CD-13-0696 |
| Journal | Cancer discovery |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
