Abstract
BackgroundMolecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.MethodsIn this study, we use publically available ChIP-Seq data on regulatory factor binding in order to link transcription factors to gene signatures defining molecular subtypes of urothelial carcinoma.ResultsWe identify PPARG and STAT3, as well as ADIRF, a novel regulator of fatty acid metabolism, as putative mediators of the SCC-like phenotype. We link the PLK1-FOXM1 axis to the rapidly proliferating Genomically Unstable and SCC-like subtypes and show that differentiation programs involving PPARG/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in UC molecular subtypes. We show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner, suggesting similarities at the gene regulatory level of these two tumor types.ConclusionsAt the gene regulatory level Urobasal, Genomically Unstable and SCC-like tumors represents three fundamentally different tumor types. Urobasal tumors maintain an apparent urothelial differentiation axis composed of PPARG/RXRA, FOXA1/GATA3 and anterior HOXA and HOXB genes. Genomically Unstable and SCC-like tumors differ from Urobasal tumors by a strong increase of proliferative activity through the PLK1-FOXM1 axis operating in both subtypes. However, whereas SCC-like tumors evade urothelial differentiation by a block in differentiation through strong downregulation of PPARG/RXRA, FOXA1/GATA3, our data indicates that Genomically Unstable tumors evade differentiation in a more dynamic manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0101-5) contains supplementary material, which is available to authorized users.
Highlights
Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes
We link the PLK1-FOXM1 axis to the rapidly proliferating Genomically Unstable (GU) and SCCL subtypes and show that differentiation programs involving peroxisome proliferator-activated receptor-gamma (PPARG)/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in Urothelial carcinoma (UC) molecular subtypes
We expand on the suggested similarities between UC and breast cancer [7], and show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner suggesting similarities at the gene regulatory level of these two tumor types
Summary
Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized. Urothelial carcinoma (UC) arises from the urinary bladder epithelium that consists of three cell layers, basal cells, transiently amplifying cells and differentiated umbrella cells. Key factors in urothelial development and differentiation have been extensively studied during the last decade These studies have shown that nuclear receptors PPARG and RXRA, as well as the transcriptional regulators FOXA1, TP63. We link the PLK1-FOXM1 axis to the rapidly proliferating GU and SCCL subtypes and show that differentiation programs involving PPARG/RXRA, FOXA1/GATA3 and HOXA/HOXB are differentially expressed in UC molecular subtypes. We expand on the suggested similarities between UC and breast cancer [7], and show that gene signatures and regulatory systems defined in urothelial carcinoma operate in breast cancer in a subtype specific manner suggesting similarities at the gene regulatory level of these two tumor types
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