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The role of proline isomerase pin1 in regulating transactivation of the androgen receptor n-terminal domain

University of British Columbia

Currently, there is no cure for patients with castration-resistant prostate cancer (CRPC). Most CRPC continues to be driven by androgen receptor (AR) signalling for growth and survival, despite androgen-deprivation therapy maintaining castrate levels of serum androgen. AR transcriptional activity is mediated entirely by its intrinsically disordered N-terminal domain (NTD) and believed to involve transiently induced structures within Tau-5 of the NTD to promote interaction with basal transcriptional machinery. The AR NTD harbours six putative binding sites for Pin1, a proline isomerase that regulates protein conformation at specific phosphorylated-Ser/Thr-Pro motifs. Since induced folding within the AR NTD is supposed to be required for transactivation, perturbation of its structure may be a promising approach to block its activity. The purpose of this study was to elucidate the role of Pin1 in regulating the transcriptional activity of AR and to test Pin1 inhibitors for CRPC. We hypothesized that Pin1 interacts with the AR NTD to regulate transactivation and that targeting Pin1 would enhance the inhibitory response of EPI compounds which specifically bind to Tau-5 in the AR NTD. We assessed Pin1 inhibitors, juglone and ATRA, for their effects on AR function using various cell-based assays. We evaluated the efficacy of ATRA in vivo, as monotherapy and combination therapy with EPI-7170, using human CRPC xenograft models. We found that targeting the isomerase activity of Pin1 reduced the transcriptional activity of AR. Pin1 interacted with the AR NTD and regulated ligand-independent transactivation by interleukin-6. The Pin1 inhibitor ATRA prevented cell proliferation driven by the constitutively active AR splice variant, AR-V7, and was synergistic with EPI compounds for inhibiting AR transcriptional activity. Furthermore, combination therapy of ATRA and EPI-7170 was effective in reducing the in vivo growth of CRPC xenografts. In summary, the isomerase function of Pin1 was essential for transactivation of the AR NTD and targeting Pin1 enhanced the potency of AR NTD inhibitors. Since there are currently no effective treatments for lethal CRPC, elucidating the molecular mechanisms which regulate the transcriptional activity of AR could aid in the development of more effective therapies for prostate cancer.

Text

2021-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/72986

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/