The androgen receptor couples promoter recruitment of RNA processing factors to regulation of alternative polyadenylation at the 3' end of transcripts

Abstract

Prostate cancer (PC) relies on androgen receptor (AR) signaling. While hormonal therapy (HT) is efficacious, most patients evolve to an incurable castration-resistant stage (CRPC). To date, most proposed mechanisms of acquired resistance to HT have focused on AR transcriptional activity. Herein, we uncover a new role for the AR in alternative cleavage and polyadenylation (APA). Inhibition of the AR by Enzalutamide globally regulates APA in PC cells, with specific enrichment in genes related to transcription and DNA topology, suggesting their involvement in transcriptome reprogramming. AR inhibition selects promoter-distal polyadenylation sites (pAs) enriched in cis-elements recognized by the cleavage and polyadenylation specificity factor (CPSF) complex. Conversely, promoter-proximal intronic pAs relying on the cleavage stimulation factor (CSTF) complex are repressed. Mechanistically, Enzalutamide induces rearrangement of APA subcomplexes and impairs the interaction between CPSF and CSTF. AR inhibition also induces co-transcriptional CPSF recruitment to gene promoters, predisposing the selection of pAs depending on this complex. Importantly, the scaffold CPSF160 protein is up-regulated in CRPC cells and its depletion represses HT-induced APA patterns. These findings uncover an unexpected role for the AR in APA regulation and suggest that APA-mediated transcriptome reprogramming represents an adaptive response of PC cells to HT.

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“…6 C), which is known to dysregulate RNA processing regulation in PC [ 24 ]. Notably, several studies have recently shown that widespread alteration of 3’-end RNA processing in PC cells contributes to tumour progression [ 48 – 51 ]. Moreover, androgen deprivation therapy in PC cells induced a general reprogramming of APA, by promoting the pattern observed in CRPC cells [ 48 ].…”

“…Notably, several studies have recently shown that widespread alteration of 3’-end RNA processing in PC cells contributes to tumour progression [ 48 – 51 ]. Moreover, androgen deprivation therapy in PC cells induced a general reprogramming of APA, by promoting the pattern observed in CRPC cells [ 48 ]. These observations suggest that APA dysregulation contributes to PC progression and to acquisition of a therapy-resistant phenotype.…”

“…Since alterations in this pathway have been linked to PC development and acquisition of a castration resistant status [ 48 – 50 ], we aimed at testing the impact of its pharmacologic inhibition on CRPC cell viability. A specific inhibitor of CPSF3, the CPSF catalytic component that operates the cleavage at the polyadenylation site [ 52 ] was recently developed [ 55 ].…”

“…7 A), similarly to what reported for tumour cells that are vulnerable to this drug [ 56 , 57 ]. By contrast, LNCaP, which are representative of a less aggressive and androgen-sensitive stage of PC [ 48 ], were much less sensitive (IC 50 > 25 µM; Fig. 7 A, Additional File 2 : Fig.…”

“…7 C). CPSF3 expression was shown to be higher in PC patients that experienced disease relapse [ 48 ]. Moreover, high expression of CPSF3 and PCF11 was significantly associated with shorter PFI and DFI in PC patients (Additional File 2 : Fig.…”