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Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression
J. Van Goubergen, M. Peřina, F. Handle, E. Morales, A. Kremer, O. Schmidt, G. Kristiansen, MV. Cronauer, FR. Santer
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
Grantová podpora
FC/2020/01
Fondation Cancer
10.55776/P36187
Austrian Science Fund
NLK
Directory of Open Access Journals
od 2017
PubMed Central
od 2007
Europe PubMed Central
od 2007
ProQuest Central
od 2007-06-01
Wiley-Blackwell Open Access Titles
od 2007
PubMed
39258426
DOI
10.1002/1878-0261.13728
Knihovny.cz E-zdroje
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- alternativní sestřih genetika účinky léků MeSH
- androgenní receptory * metabolismus genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * genetika metabolismus patologie farmakoterapie MeSH
- protein - isoformy genetika metabolismus MeSH
- protein-serin-threoninkinasy genetika metabolismus antagonisté a inhibitory MeSH
- regulace genové exprese u nádorů * účinky léků MeSH
- serin-arginin sestřihové faktory * metabolismus genetika MeSH
- sestřih RNA genetika MeSH
- tyrosinkinasy * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
Department of Experimental Biology Faculty of Science Palacký University Olomouc Czech Republic
Division of Experimental Urology Department of Urology Medical University of Innsbruck Austria
Institute of Cell Biology Biocenter Medical University of Innsbruck Austria
Citace poskytuje Crossref.org
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