CYCLIN K down-regulation induces androgen receptor gene intronic polyadenylation, variant expression and PARP inhibitor vulnerability in castration-resistant prostate cancer.
Rui SunTing WeiDonglin DingJianong ZhangSujun ChenHousheng Hansen HeLiguo WangHaojie HuangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- poor prognosis
- cell cycle
- copy number
- prostate cancer
- genome wide
- dna damage
- binding protein
- cell cycle arrest
- dna repair
- long non coding rna
- genome wide identification
- gene expression
- computed tomography
- magnetic resonance
- cell death
- transcription factor
- induced apoptosis
- cell proliferation
- magnetic resonance imaging
- radical prostatectomy
- signaling pathway
- cell therapy
- drug delivery
- drug induced
- genome wide analysis
- pi k akt
- cancer therapy
- contrast enhanced