Renal cell carcinoma (RCC) is among the 10 most common malignancies in the U.S. Clear cell RCC (ccRCC) is the most common histology. Recent analysis of ccRCC by the Cancer Genome Atlas (TCGA) demonstrates the reduced mRNA expression of several enzymes of the tricarboxylic acid (TCA) cycle. Moreover, reduced TCA enzymes expression is associated with worse prognosis. These data indicate a transcriptional program that promotes a bioenergetic shift. These studies prompted us to examine transcription factors that are known regulators of mitochondrial metabolism including the estrogen-related receptors (ERRs) and peroxisome proliferator-activated receptor γ (PPARγ) coactivators 1 (PGC-1s). Interestingly, mRNA analysis of RCC tissues and cell lines demonstrates the reduced expression of ERRγ and PGC-1α. Notably, prior analysis demonstrates putative ERR binding sites in the promoters of FH and MDH2, two genes encoding TCA enzymes with reduced expression in ccRCC. Promoter analysis of these genes with a luciferase reporter assay demonstrates that ERRγ and PGC-1α cooperate to regulate the expression of TCA enzymes indicating that reduced expression of these factors promotes reduced TCA enzyme expression in RCC.
Citation Format: EunYoung Kho, Richard Kirkman, Eun-Hee Shim, Arindam Goash, Sunil Sudarshan. Novel regulators of renal cancer metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2435. doi:10.1158/1538-7445.AM2014-2435