Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells
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 do...
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doaj-d596508e4db041fab19ab78aa8fed1fd2021-01-17T12:33:06ZengNature Publishing GroupScientific Reports2045-23222021-01-0111111210.1038/s41598-021-81164-0Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cellsManjul Rana0Jianrong Dong1Matthew J. Robertson2Cristian Coarfa3Nancy L. Weigel4Department of Molecular and Cellular Biology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineAbstract 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.https://doi.org/10.1038/s41598-021-81164-0 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Manjul Rana Jianrong Dong Matthew J. Robertson Cristian Coarfa Nancy L. Weigel |
spellingShingle |
Manjul Rana Jianrong Dong Matthew J. Robertson Cristian Coarfa Nancy L. Weigel Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells Scientific Reports |
author_facet |
Manjul Rana Jianrong Dong Matthew J. Robertson Cristian Coarfa Nancy L. Weigel |
author_sort |
Manjul Rana |
title |
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells |
title_short |
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells |
title_full |
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells |
title_fullStr |
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells |
title_full_unstemmed |
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells |
title_sort |
androgen receptor and its splice variant, ar-v7, differentially induce mrna splicing in prostate cancer cells |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-01-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-021-81164-0 |
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