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The role and regulation of PPARγ expression in muscle invasive bladder cancer

University of British Columbia

Bladder cancer is the tenth most common cancer worldwide with high rates of morbidity and mortality. Muscle-invasive bladder cancer (MIBC) is an aggressive form of the disease with limited therapeutic options. There is therefore an urgent need to develop novel therapies to treat this disease, which will require a better understanding of the biology underlying its development and progression. Peroxisome proliferator activated receptor gamma (PPARγ) is a class II nuclear receptor central in the regulation of cell metabolism, tissue differentiation, and regulation of the immune system. PPARγ is required for the normal differentiation of the urothelium and is thought to be an essential driver of the luminal subtype of MIBC. However, critical questions regarding the exact role and regulation of this transcription factor in this context remain unresolved. Here, we designed a high throughput genome-wide CRISPR knockout screen aimed to identify novel regulators of PPARG gene expression that could potentially be exploited as therapeutic targets. We identified putative positive regulators of PPARG known to be involved in cellular oxidative stress response, xenobiotic detoxification, regulation of transcription, and chromatin remodeling. In particular, the screen identified GATA3, SUPT6H, and components of the cohesin complex (SMC1A and RAD21) as regulators of PPARγ expression. PPARγ has been associated with immune evasion in MIBC, however mechanistic studies to dissect this association need to be further investigated. Using an orthotopic model of murine luminal bladder cancer we found that overexpression of Pparg was sufficient to activate its activity as a nuclear receptor, which led to impaired tumor growth as a result of T cell-mediated clearance. The negative effects of increased Pparg on tumor growth were cell autonomous, and, based on transcriptomic data, may be linked to a role for PPARγ in ferroptosis. Overall, our studies have contributed new information about a critical factor in luminal MIBC biology, which provides an important step towards the identification of novel targets for bladder cancer treatment.

Text

2023-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/77457

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/