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Updated: Jun 13, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression
Jasper Van Goubergen1, Miroslav Peřina1,2, Florian Handle3
1Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria.
Abstract:
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.
Insights
Targeting the ARV7 3'UTR in advanced prostate cancer (PC) offers a new therapeutic strategy. Inhibiting the CLK2/SRSF9 axis reduces ARV7 expression, showing promise against therapy-resistant PC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Advanced prostate cancer (PC) often develops resistance to androgen receptor signaling inhibitors (ARSI).
- Upregulation of androgen receptor (AR) splice variants, particularly AR splice variant-7 (ARV7), contributes to therapy resistance.
- The distinct 3' untranslated region (3'UTR) of ARV7 suggests unique post-transcriptional regulation mechanisms.
Purpose of the Study:
- To evaluate the therapeutic potential of targeting the ARV7 3'UTR.
- To investigate the role of a specific single nucleotide polymorphism (rs5918762) in ARV7 expression.
- To identify key regulators of ARV7 splicing and explore their inhibition as a treatment strategy.
Main Methods:
- Analysis of ARV7 expression in cellular models and patient specimens.
- Investigating the interaction between serine/arginine-rich splicing factor 9 (SRSF9) and the ARV7 3'UTR.
- Examining the role of dual specificity protein kinase CLK2 in regulating SRSF9 activity.
- Testing the efficacy of CLK inhibitors (cirtuvivint, lorecivivint) on ARV7 expression and cancer cell proliferation.
Main Results:
- A single nucleotide polymorphism, rs5918762, influences ARV7 splicing and expression.
- SRSF9 binds to the ARV7 3'UTR, promoting ARV7 inclusion via the cryptic exon 3 in the presence of the rs5918762 C allele.
- CLK2 regulates SRSF9 activity, and its inhibition decreases ARV7 expression.
- CLK inhibitors cirtuvivint and lorecivivint demonstrated potent anti-proliferative effects in both enzalutamide-naive and -resistant prostate cancer models.
Conclusions:
- Targeting the CLK2/SRSF9 axis by inhibiting CLK family kinases is a promising therapeutic strategy.
- This approach effectively reduces ARV7 expression and exhibits anti-proliferative effects in advanced, ARSI-resistant prostate cancer.
- Aberrant alternative splicing of ARV7 at the 3'UTR presents a viable therapeutic target for late-stage prostate cancer.
