Abstract
Prostate cancer (PCa) is dependent on the androgen receptor (AR). Advanced PCa is treated with an androgen deprivation therapy-based regimen; tumors develop resistance, although they typically remain AR-dependent. Expression of constitutively active AR variants lacking the ligand-binding domain including the variant AR-V7 contributes to this resistance. AR and AR-V7, as transcription factors, regulate many of the same genes, but also have unique activities. In this study, the capacity of the two AR isoforms to regulate splicing was examined. RNA-seq data from models that endogenously express AR and express AR-V7 in response to doxycycline were used. Both AR isoforms induced multiple changes in splicing and many changes were isoform-specific. Analyses of two endogenous genes, PGAP2 and TPD52, were performed to examine differential splicing. A novel exon that appears to be a novel transcription start site was preferentially induced by AR-V7 in PGAP2 although it is induced to a lesser extent by AR. The previously described AR induced promoter 2 usage that results in a novel protein derived from TPD52 (PrLZ) was not induced by AR-V7. AR, but not AR-V7, bound to a site proximal to promoter 2, and induction was found to depend on FOXA1.
Highlights
Prostate cancer (PCa) is dependent on the androgen receptor (AR)
Our current analyses reveal that AR activated by R1881 or AR-V7 induced by Dox drive the production of alternative mRNA isoforms in prostate cancer cell lines
The full-length AR contains 8 exons that encode four functional domains: the domains starting from the aminoterminus are the amino-terminal transactivation domain (NTD) encoded by exon 1, a DNA binding domain (DBD) which is encoded by exon 2 and exon 3, a flexible domain called the hinge region encoded by the 5′ portion of exon 4 and a C-terminal domain called ligand-binding domain (LBD) encoded by exons 4–834
Summary
Prostate cancer (PCa) is dependent on the androgen receptor (AR). Advanced PCa is treated with an androgen deprivation therapy-based regimen; tumors develop resistance, they typically remain AR-dependent. Metastatic PCa is treated with an androgen deprivation therapy (ADT) based regimen but eventually, these tumors develop resistance through multiple mechanisms that reactivate A R4–6 These include the expression of constitutively active AR splice variants that lack a ligandbinding domain such as AR-V76–10. Different alternative combinations of exons and splice sites generated during splicing can produce multiple transcripts and different protein sequences from a single locus This is, in part, responsible for the much greater diversity of the transcriptome and proteome than would be obtained from a single protein isoform derived from each gene[13,15,16]. RNA-seq based data of AR activity in response to androgens identified many genes whose transcription is regulated by the AR in prostate cancer[26]. Analysis of our RNA-seq data and other studies revealed differential expression of target genes
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