Abstract 53: Epigenetic silencing of krebs cycle metabolism in kidney cancer

Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC) including recent large-scale transcriptomic data demonstrating loss of tricarboxylic acid (TCA) cycle enzyme expression with aggressive tumors. Using a metabolomics/transcriptomics approach, we identified loss of mRNA expression of PGC-1α and ERR-γ is associated with tumor progression and worsened outcomes in RCC patients. PGC-1α both induces and cooperates with ERR-γ to promote TCA cycle enzyme expression. Additionally, PGC-1α reconstitution in RCC cells reverses the glycolytic phenotype and suppresses invasive phenotypes. Loss of PGC-1α and ERR-γ is through DNA and histone repressive silencing of the transcription factor PRDM16. Loss of PRDM16 is among the most prominent transcriptional changes in metastatic tumor sites. PRDM16 expression in RCC cells restorers TCA cycle enzyme expression, mitigates the Warburg phenotype, and suppresses in vivo tumorigenesis. Collectively, our data uncover a transcription factor network epigenetically silenced in renal cancer resulting in suppression of mitochondrial metabolism.

Citation Format: Eun-Young Kho, Carolina B. Livi, Phillip Buckhaults, Francesca Carobbio, Hye-Young Nam, Richard Kirkman, David Crossman, Praveen K. Vayalil, Shi Wei, Ralph J. DeBerardinis, Sunil Sudarshan. Epigenetic silencing of krebs cycle metabolism in kidney cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 53.