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CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer

Androgen receptor (AR) messenger RNA (mRNA) alternative splicing variants (AR-Vs) are implicated in castration-resistant progression of prostate cancer (PCa), although the molecular mechanism underlying the genesis of AR-Vs remains poorly understood. The CDK12 gene is often deleted or mutated in PCa...

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Autores principales: Sun, Rui, Wei, Ting, Ding, Donglin, Zhang, Jianong, Chen, Sujun, He, Housheng Hansen, Wang, Liguo, Huang, Haojie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522376/
https://www.ncbi.nlm.nih.gov/pubmed/36129942
http://dx.doi.org/10.1073/pnas.2205509119
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author Sun, Rui
Wei, Ting
Ding, Donglin
Zhang, Jianong
Chen, Sujun
He, Housheng Hansen
Wang, Liguo
Huang, Haojie
author_facet Sun, Rui
Wei, Ting
Ding, Donglin
Zhang, Jianong
Chen, Sujun
He, Housheng Hansen
Wang, Liguo
Huang, Haojie
author_sort Sun, Rui
collection PubMed
description Androgen receptor (AR) messenger RNA (mRNA) alternative splicing variants (AR-Vs) are implicated in castration-resistant progression of prostate cancer (PCa), although the molecular mechanism underlying the genesis of AR-Vs remains poorly understood. The CDK12 gene is often deleted or mutated in PCa and CDK12 deficiency is known to cause homologous recombination repair gene alteration or BRCAness via alternative polyadenylation (APA). Here, we demonstrate that pharmacological inhibition or genetic inactivation of CDK12 induces AR gene intronic (intron 3) polyadenylation (IPA) usage, AR-V expression, and PCa cell resistance to the antiandrogen enzalutamide (ENZ). We further show that AR binds to the CCNK gene promoter and up-regulates CYCLIN K expression. In contrast, ENZ decreases AR occupancy at the CCNK gene promoter and suppresses CYCLIN K expression. Similar to the effect of the CDK12 inhibitor, CYCLIN K degrader or ENZ treatment promotes AR gene IPA usage, AR-V expression, and ENZ-resistant growth of PCa cells. Importantly, we show that targeting BRCAness induced by CYCLIN K down-regulation with the PARP inhibitor overcomes ENZ resistance. Our findings identify CYCLIN K down-regulation as a key driver of IPA usage, hormonal therapy–induced AR-V expression, and castration resistance in PCa. These results suggest that hormonal therapy–induced AR-V expression and therapy resistance are vulnerable to PARP inhibitor treatment.
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spelling pubmed-95223762022-09-30 CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer Sun, Rui Wei, Ting Ding, Donglin Zhang, Jianong Chen, Sujun He, Housheng Hansen Wang, Liguo Huang, Haojie Proc Natl Acad Sci U S A Biological Sciences Androgen receptor (AR) messenger RNA (mRNA) alternative splicing variants (AR-Vs) are implicated in castration-resistant progression of prostate cancer (PCa), although the molecular mechanism underlying the genesis of AR-Vs remains poorly understood. The CDK12 gene is often deleted or mutated in PCa and CDK12 deficiency is known to cause homologous recombination repair gene alteration or BRCAness via alternative polyadenylation (APA). Here, we demonstrate that pharmacological inhibition or genetic inactivation of CDK12 induces AR gene intronic (intron 3) polyadenylation (IPA) usage, AR-V expression, and PCa cell resistance to the antiandrogen enzalutamide (ENZ). We further show that AR binds to the CCNK gene promoter and up-regulates CYCLIN K expression. In contrast, ENZ decreases AR occupancy at the CCNK gene promoter and suppresses CYCLIN K expression. Similar to the effect of the CDK12 inhibitor, CYCLIN K degrader or ENZ treatment promotes AR gene IPA usage, AR-V expression, and ENZ-resistant growth of PCa cells. Importantly, we show that targeting BRCAness induced by CYCLIN K down-regulation with the PARP inhibitor overcomes ENZ resistance. Our findings identify CYCLIN K down-regulation as a key driver of IPA usage, hormonal therapy–induced AR-V expression, and castration resistance in PCa. These results suggest that hormonal therapy–induced AR-V expression and therapy resistance are vulnerable to PARP inhibitor treatment. National Academy of Sciences 2022-09-21 2022-09-27 /pmc/articles/PMC9522376/ /pubmed/36129942 http://dx.doi.org/10.1073/pnas.2205509119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Sun, Rui
Wei, Ting
Ding, Donglin
Zhang, Jianong
Chen, Sujun
He, Housheng Hansen
Wang, Liguo
Huang, Haojie
CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title_full CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title_fullStr CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title_full_unstemmed CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title_short CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer
title_sort cyclin k down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and parp inhibitor vulnerability in castration-resistant prostate cancer
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522376/
https://www.ncbi.nlm.nih.gov/pubmed/36129942
http://dx.doi.org/10.1073/pnas.2205509119
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