Inhibition of CDK9 activity compromises global splicing in prostate cancer cells.
Alternative Splicing
Cell Line, Tumor
Cyclin-Dependent Kinase 9
/ antagonists & inhibitors
Enzyme Activation
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Male
Oligonucleotides
/ genetics
Prostatic Neoplasms
/ genetics
Protein Kinase Inhibitors
/ pharmacology
RNA Interference
RNA Splicing
RNA, Messenger
/ genetics
Receptors, Androgen
/ genetics
Spliceosomes
/ metabolism
Cyclin-dependent kinase 9
bioinformatics
o-glcnac transferase
prostate cancer
splicing
Journal
RNA biology
ISSN: 1555-8584
Titre abrégé: RNA Biol
Pays: United States
ID NLM: 101235328
Informations de publication
Date de publication:
12 11 2021
12 11 2021
Historique:
pubmed:
2
10
2021
medline:
11
3
2022
entrez:
1
10
2021
Statut:
ppublish
Résumé
Cyclin-dependent kinase 9 (CDK9) phosphorylates RNA polymerase II to promote productive transcription elongation. Here we show that short-term CDK9 inhibition affects the splicing of thousands of mRNAs. CDK9 inhibition impairs global splicing and there is no evidence for a coordinated response between the alternative splicing and the overall transcriptome. Alternative splicing is a feature of aggressive prostate cancer (CRPC) and enables the generation of the anti-androgen resistant version of the ligand-independent androgen receptor, AR-v7. We show that CDK9 inhibition results in the loss of AR and AR-v7 expression due to the defects in splicing, which sensitizes CRPC cells to androgen deprivation. Finally, we demonstrate that CDK9 expression increases as PC cells develop CRPC-phenotype both
Identifiants
pubmed: 34592899
doi: 10.1080/15476286.2021.1983287
pmc: PMC8782174
doi:
Substances chimiques
Oligonucleotides
0
Protein Kinase Inhibitors
0
RNA, Messenger
0
Receptors, Androgen
0
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
722-729Subventions
Organisme : NCI NIH HHS
ID : R01 CA240290
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA237939
Pays : United States
Références
J Med Chem. 2020 Nov 25;63(22):13228-13257
pubmed: 32866383
Genome Biol. 2014;15(12):550
pubmed: 25516281
Clin Cancer Res. 2020 Feb 15;26(4):922-934
pubmed: 31699827
Neoplasia. 2017 Aug;19(8):649-658
pubmed: 28732212
Nature. 2011 Sep 11;478(7367):64-9
pubmed: 21909114
Nat Chem Biol. 2018 Feb;14(2):163-170
pubmed: 29251720
Nat Rev Mol Cell Biol. 2012 Apr 23;13(5):312-21
pubmed: 22522719
Cancer Discov. 2020 Mar;10(3):351-370
pubmed: 32071145
Nat Commun. 2020 Apr 29;11(1):2089
pubmed: 32350277
Elife. 2015 Jun 17;4:e06535
pubmed: 26083714
Sci Rep. 2020 Oct 12;10(1):16992
pubmed: 33046784
Oncogene. 2015 Jul;34(28):3744-50
pubmed: 25241896
Mol Cancer Res. 2020 Oct;18(10):1512-1521
pubmed: 32611550
J Exp Clin Cancer Res. 2018 Feb 23;37(1):36
pubmed: 29471852
Cell. 2018 Sep 20;175(1):171-185.e25
pubmed: 30146162
J Clin Invest. 2019 Jan 2;129(1):192-208
pubmed: 30334814
Cancer Res. 2009 Jan 1;69(1):16-22
pubmed: 19117982
Oncotarget. 2019 Dec 10;10(65):6934-6943
pubmed: 31857848
Nucleic Acids Res. 2020 Jun 4;48(10):5656-5669
pubmed: 32329777
Bioinformatics. 2021 Mar 27;:
pubmed: 33772584
Theranostics. 2019 Apr 12;9(8):2183-2197
pubmed: 31149037
Cancer Res. 2013 Aug 15;73(16):5277-87
pubmed: 23720054
Nat Rev Clin Oncol. 2018 Nov;15(11):663-675
pubmed: 30135575
PLoS One. 2013 May 28;8(5):e65016
pubmed: 23724116
Nat Rev Mol Cell Biol. 2017 Jul;18(7):452-465
pubmed: 28488703
Mol Cancer Res. 2021 Apr;19(4):555-564
pubmed: 33472950
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Mol Cancer Ther. 2009 Feb;8(2):324-32
pubmed: 19174555
Genome Biol. 2001;2(10):RESEARCH0041
pubmed: 11597333
Cell. 2015 Nov 5;163(4):1011-25
pubmed: 26544944
Blood. 2017 Mar 30;129(13):1876-1878
pubmed: 28126927
J Biol Chem. 2019 Feb 15;294(7):2211-2231
pubmed: 30626734
Nat Chem Biol. 2020 Jul;16(7):716-724
pubmed: 32572259
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601
pubmed: 25480548