Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression
In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant‐7 (ARV7) is clinically the most relevant and has a dist...
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| Format: | Article |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13728 |
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| author | Jasper Van Goubergen Miroslav Peřina Florian Handle Elisa Morales Anika Kremer Oliver Schmidt Glen Kristiansen Marcus V. Cronauer Frédéric R. Santer |
| author_facet | Jasper Van Goubergen Miroslav Peřina Florian Handle Elisa Morales Anika Kremer Oliver Schmidt Glen Kristiansen Marcus V. Cronauer Frédéric R. Santer |
| author_sort | Jasper Van Goubergen |
| collection | DOAJ |
| description | In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant‐7 (ARV7) is clinically the most relevant and has a distinct 3′ untranslated region (3′UTR) compared to the AR full‐length variant, suggesting a unique post‐transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3′UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine‐rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2‐like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti‐proliferative effects in enzalutamide‐treated or ‐naive PC models. Thus, targeting aberrant alternative splicing at the 3′UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI‐resistant PC. |
| format | Article |
| id | doaj-art-4fb76db18e8146848ae2fe69ecb8b28c |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-4fb76db18e8146848ae2fe69ecb8b28c2025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119249651810.1002/1878-0261.13728Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expressionJasper Van Goubergen0Miroslav Peřina1Florian Handle2Elisa Morales3Anika Kremer4Oliver Schmidt5Glen Kristiansen6Marcus V. Cronauer7Frédéric R. Santer8Division of Experimental Urology, Department of Urology Medical University of Innsbruck AustriaDivision of Experimental Urology, Department of Urology Medical University of Innsbruck AustriaInstitute of Pathology, Neuropathology & Molecular Pathology Medical University of Innsbruck AustriaDivision of Experimental Urology, Department of Urology Medical University of Innsbruck AustriaInstitute of Pathology University Hospital Bonn GermanyInstitute of Cell Biology, Biocenter Medical University of Innsbruck AustriaInstitute of Pathology University Hospital Bonn GermanyInstitute of Pathology University Hospital Bonn GermanyDivision of Experimental Urology, Department of Urology Medical University of Innsbruck AustriaIn advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant‐7 (ARV7) is clinically the most relevant and has a distinct 3′ untranslated region (3′UTR) compared to the AR full‐length variant, suggesting a unique post‐transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3′UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine‐rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2‐like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti‐proliferative effects in enzalutamide‐treated or ‐naive PC models. Thus, targeting aberrant alternative splicing at the 3′UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI‐resistant PC.https://doi.org/10.1002/1878-0261.137283′ untranslated regionallele‐specific regulationandrogen receptor splice variant 7dual specificity protein kinase CLK2serine/arginine‐family of splicing factorssplicing inhibitors |
| spellingShingle | Jasper Van Goubergen Miroslav Peřina Florian Handle Elisa Morales Anika Kremer Oliver Schmidt Glen Kristiansen Marcus V. Cronauer Frédéric R. Santer Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression Molecular Oncology 3′ untranslated region allele‐specific regulation androgen receptor splice variant 7 dual specificity protein kinase CLK2 serine/arginine‐family of splicing factors splicing inhibitors |
| title | Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression |
| title_full | Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression |
| title_fullStr | Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression |
| title_full_unstemmed | Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression |
| title_short | Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression |
| title_sort | targeting the clk2 srsf9 splicing axis in prostate cancer leads to decreased arv7 expression |
| topic | 3′ untranslated region allele‐specific regulation androgen receptor splice variant 7 dual specificity protein kinase CLK2 serine/arginine‐family of splicing factors splicing inhibitors |
| url | https://doi.org/10.1002/1878-0261.13728 |
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