Ppar Gamma Is Dispensable For Clear Cell Renal Cell Carcinoma Progression

Objective: Clear cell renal cell carcinoma (ccRCC) is a subtype of kidney cancer defined by robust lipid accumulation, which prior studies have indicated plays an important role in tumor progression. We hypothesized that the peroxisome proliferator-activated receptor gamma (PPAR gamma), detected in both ccRCC tumors and cell lines, promotes lipid storage in ccRCC and contributes to tumorigenesis in this setting. PPAR gamma transcriptionally regulates a number of genes involved in lipid and glucose metabolism in adipocytes, yet its role in ccRCC has not been described. The objective of this study was to elucidate endogenous PPAR gamma function in ccRCC cells.Methods and results: Using chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), we found that PPAR gamma and its heterodimer RXR occupy the canonical DR1 PPAR binding motif at approximately 1000 locations throughout the genome that can be subdivided into adiposeshared and ccRCC-specific sites. CRISPR-Cas9 mediated, loss-of-function studies determined that PPAR gamma is dispensable for viability, proliferation, and migration of ccRCC cells in vitro and in vivo. Also, surprisingly, PPAR gamma deletion had little effect on the robust lipid accumulation that typifies the "clear cell" phenotype of kidney cancer.Conclusion: Our results suggest that PPAR gamma plays neither a tumor suppressive nor oncogenic role in advanced ccRCC, and thus single-agent therapeutics targeting PPAR gamma are unlikely to be effective for the treatment of this disease. The unique cistrome of PPAR gamma in ccRCC cells demonstrates the importance of cell type in determining the functions of PPAR gamma. (C) 2018 The Authors. Published by Elsevier GmbH.