Cell-Intrinsic Tumorigenic Functions of PPARγ in Bladder Urothelial Carcinoma
- 11 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 19 (4), 598-611
- https://doi.org/10.1158/1541-7786.mcr-20-0189
Abstract
The role of peroxisome proliferator-activated receptor gamma (PPARγ) has been well characterized in the developmental process of adipogenesis, yet its aberrant expression patterns and functions in cancer subtypes are less understood. While PPARγ has been recently demonstrated to play non-cell-autonomous roles in promoting bladder urothelial carcinoma (UC) progression, underlying mechanisms of the cell-intrinsic oncogenic activity remain unknown. Here, we report robust expression and nuclear accumulation of PPARγ in 47% of UC patient samples, exceeding mRNA expression patterns published by The Cancer Genome Atlas. In vitro assays revealed for the first time that treatment of UC cells with PPARγ inverse agonist or PPARG knockout by CRISPR-Cas9 reduces proliferation, migration, and invasion of multiple established UC cell lines, most strongly in those characterized by PPARG genomic amplification or activating mutations of RXRA, the obligate heterodimer of PPARγ. Through genome-wide approaches including ChIP- and RNA-seq, we define a novel set of PPARγ-regulated genes in UC, including Sonic Hedgehog (SHH). Similar to PPARγ, genetic inhibition of SHH reduces -proliferation and motility. Finally, we demonstrate the PPARγ dependency of UC tumors in vivo by genetic and pharmacological PPARγ inhibition in subcutaneous xenografts. Collectively, our data indicate that PPARγ promotes UC progression in a subset of patients, at least in part, through cell-autonomous mechanisms linked to SHH signaling. Implications: Genome wide analysis of DNA binding sites for oncogenic factor PPARγ revealed SHH as a novel downstream target involved in UC progression, providing important insight into the tumorigenic nature and molecular mechanism of PPARγ signaling in UC.Keywords
Other Versions
Funding Information
- Belgian American Education Fellowship (P32HD083185, F31CA206381)
- Belgian American Education Fellowship (R35CA220483)
- Belgian American Education Fellowship (R01 DK098542)
- Belgian American Education Fellowship (R35CA220483, NCIPO1CA104838)
This publication has 50 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort studyDiabetologia, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- Risk of Bladder Cancer Among Diabetic Patients Treated With PioglitazoneDiabetes Care, 2011
- Expression analysis of proline rich 15 (Prr15) in mouse and human gastrointestinal tumorsMolecular Carcinogenesis, 2010
- Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and MacrophagesMolecular and Cellular Biology, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scaleGenes & Development, 2008
- Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factorCell, 1994