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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Main Authors: Manjul Rana, Jianrong Dong, Matthew J. Robertson, Cristian Coarfa, Nancy L. Weigel
Format: Article
Language:English
Published: Nature Publishing Group 2021-01-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-81164-0
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spelling 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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