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Status |
Public on Dec 07, 2017 |
Title |
Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
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 bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers. Structure-function studies indicate the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In urothelium, we find PPAR agonism is sufficient to drive growth factor independent growth, but only after deletion of the tumor suppressors Kdm6a and Trp53. Similarly, mutant RXRA stimulates growth factor independent growth, in a manner reversible by PPAR inhibition. These studies reveal a pro-tumorigenic interaction between loss of tumor suppressors and PPAR activation and implicate PPARs as targetable drivers of bladder cancer.
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Overall design |
Two independent bladder cancer cell lines, JMSU-1 and 575A, were transfected with retrovirus to generate stable cell lines expressing either human wild-type RXRA (RXRAwt) or a mutant form of RXRA, RXRA S427F (RXRAS427F). RNA-seq was performed in biological triplicate on RXRAwt-expressing cells treated with vehicle or the PPARG agonist pioglitazone (pio), and RXRAS427F-expressing cells treated with vehicle. Fragments were sequenced on an Illumina HiSeq-2500 or HiSeq-3000. Transcriptomes in the wild-type and S427F conditions were compared to establish a causal role of the RXRA hot-spot mutation S427F in the hyper-activation of PPAR singling.
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Contributor(s) |
Halstead AM, Arora VK, Schriefer A |
Citation(s) |
29143738 |
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Submission date |
Dec 05, 2017 |
Last update date |
May 15, 2019 |
Contact name |
Vivek K Arora |
E-mail(s) |
arorav@wustl.edu
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Organization name |
Washington University School of Medicine
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Street address |
660 S Euclid Ave
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City |
St. Louis |
State/province |
MO |
ZIP/Postal code |
63110 |
Country |
USA |
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Platforms (1) |
GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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Samples (16)
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This SubSeries is part of SuperSeries: |
GSE107783 |
Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors |
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Relations |
BioProject |
PRJNA421310 |
SRA |
SRP126243 |