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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-09, Vol.119 (39), p.e2205509119-e2205509119
• Main Authors: Sun, Rui, Wei, Ting, Ding, Donglin, Zhang, Jianong, Chen, Sujun, He, Housheng Hansen, Wang, Liguo, Huang, Haojie
• Format: Article
• Language: English
• Subjects: Alternative splicing; Androgen Antagonists - pharmacology; Androgen receptors; Androgens; Antineoplastic Agents - pharmacology; Benzamides - pharmacology; Biological Sciences; Castration; Cell Line, Tumor; Cyclins - genetics; Down-Regulation; Drug Resistance, Neoplasm - genetics; Gene expression; Homologous recombination; Homologous recombination repair; Homology; Humans; Inactivation; Inhibitors; Introns; Male; mRNA; Nitriles - pharmacology; Phenylthiohydantoin - pharmacology; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Polyadenylation; Polyadenylation - genetics; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Receptors; Receptors, Androgen - genetics; RNA, Messenger - genetics; Splicing; Therapy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2205509119

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 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 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 gene promoter and up-regulates CYCLIN K expression. In contrast, ENZ decreases AR occupancy at the gene promoter and suppresses CYCLIN K expression. Similar to the effect of the CDK12 inhibitor, CYCLIN K degrader or ENZ treatment promotes 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.