-
Something wrong with this record ?
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
Language English Country United States
Document type Journal Article
Grant support
FC/2020/01
Fondation Cancer
10.55776/P36187
Austrian Science Fund
NLK
Directory of Open Access Journals
from 2017
PubMed Central
from 2007
Europe PubMed Central
from 2007
ProQuest Central
from 2007-06-01
Wiley-Blackwell Open Access Titles
from 2007
- MeSH
- 3' Untranslated Regions genetics MeSH
- Alternative Splicing genetics drug effects MeSH
- Receptors, Androgen * metabolism genetics MeSH
- Polymorphism, Single Nucleotide genetics MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms * genetics metabolism pathology drug therapy MeSH
- Protein Isoforms genetics metabolism MeSH
- Protein Serine-Threonine Kinases genetics metabolism antagonists & inhibitors MeSH
- Gene Expression Regulation, Neoplastic * drug effects MeSH
- Serine-Arginine Splicing Factors * metabolism genetics MeSH
- RNA Splicing genetics MeSH
- Protein-Tyrosine Kinases * genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article 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
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc25010131
- 003
- CZ-PrNML
- 005
- 20250429135141.0
- 007
- ta
- 008
- 250415s2025 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1002/1878-0261.13728 $2 doi
- 035 __
- $a (PubMed)39258426
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Van Goubergen, Jasper $u Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria
- 245 10
- $a Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression / $c J. Van Goubergen, M. Peřina, F. Handle, E. Morales, A. Kremer, O. Schmidt, G. Kristiansen, MV. Cronauer, FR. Santer
- 520 9_
- $a 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.
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 12
- $a serin-arginin sestřihové faktory $x metabolismus $x genetika $7 D000068103
- 650 12
- $a nádory prostaty $x genetika $x metabolismus $x patologie $x farmakoterapie $7 D011471
- 650 12
- $a tyrosinkinasy $x genetika $x metabolismus $7 D011505
- 650 12
- $a androgenní receptory $x metabolismus $x genetika $7 D011944
- 650 12
- $a regulace genové exprese u nádorů $x účinky léků $7 D015972
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a protein-serin-threoninkinasy $x genetika $x metabolismus $x antagonisté a inhibitory $7 D017346
- 650 _2
- $a alternativní sestřih $x genetika $x účinky léků $7 D017398
- 650 _2
- $a sestřih RNA $x genetika $7 D012326
- 650 _2
- $a 3' nepřekládaná oblast $x genetika $7 D020413
- 650 _2
- $a jednonukleotidový polymorfismus $x genetika $7 D020641
- 650 _2
- $a protein - isoformy $x genetika $x metabolismus $7 D020033
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Peřina, Miroslav $u Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria $u Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Czech Republic
- 700 1_
- $a Handle, Florian $u Institute of Pathology, Neuropathology & Molecular Pathology, Medical University of Innsbruck, Austria
- 700 1_
- $a Morales, Elisa $u Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria
- 700 1_
- $a Kremer, Anika $u Institute of Pathology, University Hospital Bonn, Germany
- 700 1_
- $a Schmidt, Oliver $u Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Austria
- 700 1_
- $a Kristiansen, Glen $u Institute of Pathology, University Hospital Bonn, Germany
- 700 1_
- $a Cronauer, Marcus V $u Institute of Pathology, University Hospital Bonn, Germany
- 700 1_
- $a Santer, Frédéric R $u Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria $1 https://orcid.org/0000000245916368
- 773 0_
- $w MED00167281 $t Molecular oncology $x 1878-0261 $g Roč. 19, č. 2 (2025), s. 496-518
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/39258426 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20250415 $b ABA008
- 991 __
- $a 20250429135137 $b ABA008
- 999 __
- $a ok $b bmc $g 2311483 $s 1247212
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2025 $b 19 $c 2 $d 496-518 $e 20240911 $i 1878-0261 $m Molecular oncology $n Mol Oncol $x MED00167281
- GRA __
- $a FC/2020/01 $p Fondation Cancer
- GRA __
- $a 10.55776/P36187 $p Austrian Science Fund
- LZP __
- $a Pubmed-20250415