Abstract A1-68: The long noncoding RNA SNHG18 promotes PPARγ function and luminal gene expression in muscle-invasive bladder cancer
Authors: Ochoa Andrea E. , Zhang Jianping , Choi Woonyoung , Malouf Gabriel G. , Thompson Erika J. , Weinstein John N. , Tannir Nizar M. , Dinney Colin , McConkey David J. , Su Xiaoping 
Published: November 2015

Long noncoding RNAs (lncRNAs) are emerging as important drivers of disease progression and have been shown to modulate gene expression at several levels. While many lncRNAs have been discovered, the molecular functions of a majority of identified lncRNAs are still poorly understood. Recent studies in muscle-invasive bladder cancer (MIBC) identified intrinsic molecular subtypes at the mRNA level, however the role of non-coding RNAs in the context of subtypes has not been explored. Therefore, the overall goal of this study was to obtain a deeper understanding of the lncRNAs that contribute to the molecular mechanisms that underlie the intrinsic subtypes of MIBC. In this study, we utilized TCGA's RNA-sequencing data to extract whole genome lncRNA expression from 211 MIBCs. Using an unsupervised approach, consensus clustering of lncRNA expression identified two intrinsic subtypes of MIBCs, which were synonymous with the intrinsic basal and luminal subtypes discovered through mRNA expression profiling. Previous data has shown PPARγ to be amplified in approximately 15% of luminal MIBCs, and luminal MIBCs are enriched with an active PPARγ mRNA expression signature. To further study the lncRNAs associated with the luminal subtype, cell lines were exposed to rosiglitazone, a PPARγ agonist, and RNA-sequencing was performed. Gene set enrichment analysis (GSEA) confirmed lncRNAs up-regulated after exposure to rosiglitazone were highly expressed in luminal MIBCs. Differential expression analysis revealed SNHG18 to be up-regulated after PPARγ activation, and to be highly expressed in luminal MIBCs. RNA immunoprecipitation studies confirmed that SNHG18 is directly bound by PPARγ, and subsequent knockdown of SNHG18 resulted in decreased expression of several luminal PPARγ target genes including uroplakins and fibroblast growth factor receptor-3 (FGFR3). Currently, FGFR3 is an important therapeutic target in MIBCs with activating mutations occurring in approximately 17% of cases. Overall, we have identified a novel lncRNA, SNHG18, to be a co-activator of PPARγ that controls downstream expression of several luminal target genes. The results suggest that SNHG18 could potentially serve as a predictive biomarker, as a possible drug target to increase the efficiency of FGFR3 targeted therapies, or as a therapeutic target in luminal MIBC.

Citation Format: Andrea E. Ochoa, Jianping Zhang, Woonyoung Choi, Gabriel G. Malouf, Erika J. Thompson, John N. Weinstein, Nizar M. Tannir, Colin Dinney, David J. McConkey, Xiaoping Su. The long noncoding RNA SNHG18 promotes PPARγ function and luminal gene expression in muscle-invasive bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-68.