Reference - Detail
| RRC ID | 76469 |
|---|---|
| Author | Shelar S, Shim EH, Brinkley GJ, Kundu A, Carobbio F, Poston T, Tan J, Parekh V, Benson D, Crossman DK, Buckhaults PJ, Rakheja D, Kirkman R, Sato Y, Ogawa S, Dutta S, Velu SE, Emberley E, Pan A, Chen J, Huang T, Absher D, Becker A, Kunick C, Sudarshan S. |
| Title | Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer. |
| Journal | Clin Cancer Res |
| 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. |
| Volume | 24(24) |
| Pages | 6433-6446 |
| Published | 2018-12-15 |
| DOI | 10.1158/1078-0432.CCR-18-1727 |
| PII | 1078-0432.CCR-18-1727 |
| PMID | 30108105 |
| PMC | PMC6295227 |
| MeSH | Alcohol Oxidoreductases / antagonists & inhibitors Alcohol Oxidoreductases / genetics* Alcohol Oxidoreductases / metabolism* Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Cell Line, Tumor Cell Movement / genetics Disease Models, Animal Epigenesis, Genetic* Gene Expression Gene Knockdown Techniques Glutarates / metabolism* Histones / metabolism Humans Kidney Neoplasms / drug therapy Kidney Neoplasms / genetics* Kidney Neoplasms / metabolism* Kidney Neoplasms / pathology Methylation Molecular Targeted Therapy Phenotype RNA, Small Interfering / genetics Xenograft Model Antitumor Assays |
| IF | 10.107 |
| Resource | |
| Human and Animal Cells | OS-RC-2(RCB0735) |