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Updated: Nov 21, 2025
Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Androgen receptor and its splice variant, AR-V7, differentially induce mRNA splicing in prostate cancer cells
Manjul Rana1, Jianrong Dong1,2,3, Matthew J Robertson1,2
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
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.
Insights
Androgen receptor (AR) and its variant AR-V7 differentially regulate gene splicing in prostate cancer. Understanding these distinct splicing activities is crucial for developing targeted therapies against treatment-resistant AR-dependent tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) relies on the androgen receptor (AR) for growth.
- Advanced PCa treatments like androgen deprivation therapy often lead to resistance.
- AR variants, such as AR-V7, contribute to treatment resistance while tumors remain AR-dependent.
Purpose of the Study:
- To investigate and compare the splicing regulatory capacities of AR and the AR-V7 variant.
- To identify isoform-specific changes in gene splicing induced by AR and AR-V7.
Main Methods:
- Utilized RNA-sequencing (RNA-seq) on models endogenously expressing AR and models expressing AR-V7.
- Analyzed differential splicing events in endogenous genes, specifically PGAP2 and TPD52.
- Examined AR and AR-V7 binding near gene promoters and the role of FOXA1.
Main Results:
- Both AR and AR-V7 induced significant changes in gene splicing, with many being isoform-specific.
- AR-V7 preferentially induced a novel exon in PGAP2, suggesting a new transcription start site.
- AR, but not AR-V7, induced a previously described promoter usage in TPD52, dependent on FOXA1.
Conclusions:
- AR and AR-V7 exhibit distinct roles in regulating gene splicing.
- These isoform-specific splicing alterations may contribute to the development of treatment resistance in prostate cancer.
- Further research into these differential splicing mechanisms could reveal new therapeutic targets.
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