GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE107734 Query DataSets for GSE107734
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
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.
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.
Contributor(s) Halstead AM, Arora VK, Schriefer A
Citation(s) 29143738
Submission date Dec 05, 2017
Last update date May 15, 2019
Contact name Vivek K Arora
Organization name Washington University School of Medicine
Street address 660 S Euclid Ave
City St. Louis
State/province MO
ZIP/Postal code 63110
Country USA
Platforms (1)
GPL21290 Illumina HiSeq 3000 (Homo sapiens)
Samples (16)
GSM2877292 Input_WT_A
GSM2877293 Input_WT_B
GSM2877294 Input_S427F_A
This SubSeries is part of SuperSeries:
GSE107783 Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors
BioProject PRJNA421310
SRA SRP126243

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE107734_H3K27Ac_S427F_Rep1_pooled_peaks-sorted-optimum.narrowPeak.gz 515.3 Kb (ftp)(http) NARROWPEAK
GSE107734_H3K27Ac_S427F_vs_H3K27Ac_WT.broadPeak.gz 221.6 Kb (ftp)(http) BROADPEAK
GSE107734_H3K27Ac_WT_Rep1_pooled_peaks-sorted-optimum.narrowPeak.gz 583.7 Kb (ftp)(http) NARROWPEAK
GSE107734_RXRA_S427F_Rep1_pooled_peaks-sorted-optimum.narrowPeak.gz 34.7 Kb (ftp)(http) NARROWPEAK
GSE107734_RXRA_WT_Rep1_pooled_peaks-sorted-optimum.narrowPeak.gz 69.8 Kb (ftp)(http) NARROWPEAK
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap