Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

M. Celeste Simon

Abstract

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has a well-characterized role in the developmental process of adipogenesis and transcriptional regulation of lipid metabolism. However, its expression patterns and functions in various cancer subtypes are less understood. My studies investigate the role of PPARγ in two distinct cancers of the urinary tract: clear cell renal cell carcinoma (ccRCC) and bladder urothelial carcinoma (UC). In ccRCC, I hypothesized that PPARγ activity contributes to the aberrant lipid accumulation phenotype characteristic of this disease, thereby promoting tumor progression. Through ChIP-seq, I demonstrated that PPARγ and its heterodimeric DNA binding partner retinoid X receptor (RXR) occupy both adipose-shared and ccRCC-specific sites throughout the genome. However, based on a number of in vitro and in vivo assays evaluating ccRCC viability, proliferation, migration, and effects on lipid metabolism, I concluded that PPARγ was dispensable for these processes and ccRCC progression. I also studied the role of PPARγ in UC, a cancer which displays copy number amplification and mRNA overexpression of PPARG or RXRA in ~30% of

tumors. In contrast to the results obtained in ccRCC, I demonstrated that genetic and pharmacological inhibition of PPARγ reduces tumor growth via cell cycle arrest. Furthermore, I identified a candidate list of PPARγ-regulated genes in UC based on ChIP- and RNA-seq analyses of cell culture models, as well as gene expression data from primary patient samples. Together, my studies illuminate the remarkable cell type-specific functions of PPARγ in urinary tract cancers, and provide rationale for the pharmacological targeting of its transcriptional effectors in a subset of tumors.

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