Abstract 89: Pin1 suppresses androgen receptor activity

Abstract

Abstract Reactivation of the androgen receptor (AR) is the hallmark of prostate cancer (PCa) progression to the castration resistant prostate cancer (CRPC) phenotype. Currently, treatment for CRPC strives to impede the full-length AR (AR-FL) from becoming activated through targeting the ligand binding domain (LBD) via androgen deprivation therapy or treatment with antiandrogens. However, these options can give rise to AR-variants (AR-Vs) that lack the LBD and are unresponsive to treatment. Therefore, targeting the N-terminus of AR, which is conserved between AR-FL and AR-Vs, is critical for identifying new treatment options. Phosphorylation of serine 81 (AR-pS81) in the N-terminus of AR is critical for AR activation, stability and recruitment to the chromatin. Similar phosphorylation sites can be observed in the N-terminus of both AR-FL and AR-Vs. Expression of Pin1, a proline isomerase, exhibits a strong correlation with progression and relapse of PCa. Also, suppression of Pin1 in PCa decreases cell proliferation rates, suggesting that Pin1 may play a pivotal role in PCa progression. Pin1 isomerizes proline residues from trans to cis when the adjacent serine/threonine residue is phosphorylated. Dephosphorylation by phosphatases occurs when a pS-P motif is in the trans conformation. Therefore, Pin1 isomerization of AR pS81-P82 from trans to cis could prevent dephosphorylation and result in constitutive or enhanced AR activity. Stable cell lines with Pin1 knockdown were generated via shRNA targeting the 5′ UTR of Pin1 that express either AR-FL and/or AR-Vs. Pin1 knockdown was confirmed by western blots, and AR activity was monitored by expression of several AR regulated genes. Additionally, AR recruitment to chromatin was assayed by ChIP and Re-Chip. Loss of Pin1 resulted in a 60% reduction of endogenous PSA expression, and AR was unable to induce PSA expression when treated with androgens. However, suppression of AR activity was not due to decreased recruitment of AR to chromatin. Phosphorylation of AR-pS81 was decreased by loss of Pin1, while protein stability and mRNA expression was not altered. These data suggest that Pin1 may play a critical role in regulating the transcriptional activity of AR by altering the accessibility of AR to interact with transcriptional machinery needed to maintain AR activity. (Funding for this project was provided by the T.J. Martell Foundation). Citation Format: Travis Van der Steen, Haojie Huang, Donald Tindall. Pin1 suppresses androgen receptor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 89. doi:10.1158/1538-7445.AM2015-89