Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial Proliferation
- Washington University School of Medicine, United States
Abstract
RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from the TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of human bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer.
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Funding
Damon Runyon Cancer Research Foundation (Clinical Investigator)
- Vivek K Arora
Cancer Research Foundation (Young Investigator)
- Vivek K Arora
National Cancer Institute (T32 CA113275)
- Angela M Halstead
National Center for Advancing Translational Sciences (UL1TR000448)
- Vivek K Arora
National Cancer Institute (P30 CA91842)
- Andrew Schriefer
National Institute of Diabetes and Digestive and Kidney Diseases (U54DK104279)
- Chiraag D Kapadia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were performed in accordance with institutional guidelines and current NIH policies and were approved by the Washington University School of Medicine Institutional Animal Care and Use Committee protocol #20140186.
Copyright
© 2017, Halstead et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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