Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE107783 | GEO | 2017/12/07
SECONDARY ACCESSION(S): PRJNA421354
REPOSITORIES: GEO
Similar Datasets
Project description:RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from 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.
| S-EPMC5720590 | biostudies-literature
Project description: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.
2017-12-07 | GSE107735 | GEO
Project description: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.
2017-12-07 | GSE107734 | GEO
Project description:Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors
| PRJNA421354 | ENA
Project description:Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation
| PRJNA421314 | ENA
Project description:Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation
| PRJNA421310 | ENA
Project description:Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-β/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and tumour immune response, and are essential components in tumour progression and metastasis. As such, they have become a target for cancer therapy research. In this review, we discussed the current state of knowledge on the involvement of PPARs in cancer, including their role in tumourigenesis, the impact of PPARs in tumour microenvironment and the potential of using PPARs combinational therapy to treat cancer by targeting essential signal pathways, or as adjuvants to boost the effects of current chemo and immunotherapies. Our review highlights the complexity of PPARs in cancer and the need for a better understanding of the mechanism in order to design effective cancer therapies.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a major cause of chronic liver disease worldwide. Concurrent to an increase in NAFLD prevalence, there is an increase in the obesity epidemic and the correlated insulin-resistant state. It is a challenge to diagnose NAFLD because many patients are asymptomatic until the later stages of disease. The most common symptoms include fatigue, malaise, and discomfort in the right upper quadrant. The major and most accurate tool to clinically diagnose NAFLD is a liver biopsy, followed by histological analysis. However, this procedure is invasive and often carries a high risk of complications. Currently, there are no officially approved medications for the treatment of NAFLD. Although lifestyle modifications with proper diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for many patients. Effective pharmacological treatments are still lacking; therefore, additional research to identify novel drugs is clearly warranted. PPARs are promising drug targets for the management of NAFLD and its related conditions of type 2 diabetes mellitus and cardiovascular disease. In this review, we provide an overview of recent studies on the association of PPARs and NAFLD.
| S-EPMC5735692 | biostudies-literature
Project description:Peroxisome proliferator-activated receptors (PPARs) are members of nuclear transcription factors. The functions of the PPAR family (PPARA, PPARD, and PPARG) and their coactivators (PPARGC1A and PPARGC1B) in maintenance of lipid and glucose homeostasis have been unveiled. However, the roles of PPARs in cancer development remain elusive. In this work, we made use of 11,057 samples across 33 TCGA tumor types to analyze the relationship between PPAR transcriptional expression and tumorigenesis as well as drug sensitivity. We performed multidimensional analyses on PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B, including differential expression analysis in pan-cancer, immune subtype analysis, clinical analysis, tumor purity analysis, stemness correlation analysis, and drug responses. PPARs and their coactivators expressed differently in different types of cancers, in different immune subtypes. This analysis reveals various expression patterns of the PPAR family at a level of pan-cancer and provides new clues for the therapeutic strategies of cancer.
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Project description:The topic of peroxisome proliferator-activated receptors has been developed in the field of hepatology allowing envisaging therapeutic strategies for the most frequent chronic liver diseases such as chronic infection with hepatitis C virus (HCV). PPARs contribute to wide physiological processes within the liver such as lipid/glucid metabolisms, inflammatory response, cell differentiation, and cell cycle. In vitro experiments and animal studies showed that PPAR? discloses anti-inflammatory property, and PPAR? discloses anti-inflammatory, antifibrogenic, and antiproliferative properties in the liver. Experimental and human studies showed impaired PPARs expression and function during HCV infection. The available nonhepatotoxic agonists of PPARs may constitute a progress in the therapeutic management of patients chronically infected with HCV.
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