Abstract 3927: Loss of bHLH transcription factor Id4 modulates androgen receptor activity in prostate cancer progression

Abstract

Abstract Inhibitor of differentiation 4 (Id4), a crucial developmental gene also expressed in the normal prostate, has been shown to act as a tumor suppressor in prostate cancer. Promoter hypermethylation of Id4 is observed in several advanced stage cancers including prostate cancer. The loss of Id4 expression correlates with androgen independent prostate cancer progression. Our studies suggest that Id4 plays a crucial role in mediating the transition from androgen dependent to androgen independent prostate cancer by mediating the AR axis potential and reprogramming several cellular mechanisms including migration, senescence and proliferation. Stable transfection of a full length Id4 plasmid into the androgen-independent prostate cancer cell line DU145 resulted in re-expression of AR and downstream AR response gene PSA. Id4 transfected cells also observed an androgen regulated rate of proliferation in responsive to treatment with AR antagonist, Casodex. AR antagonism also significantly reduced the rate of migration as observed by a scratch wound assay. Under closer observation, AR antagonist treatment with Casodex also inhibited translocation of AR to the nucleus of DU145 cells as observed by immunofluorescence. Previous studies in our laboratory have demonstrated that DU145+Id4 transfected cells undergo a significant level of senescence (∼ 32%) compared to normal DU145 cells (∼ 4%). Treatment of DU145+Id4 cells with the AR antagonist Casodex demonstrate that the rate of senescence in DU145+Id4 transfected cells is closely related to inhibition of AR activity. Our results suggest that Id4 may play a crucial role in the loss of AR activity in advanced stage prostate cancer progression. These results also suggest that the antagonism of AR nuclear translocation post Id4 induction closely regulates the rate of proliferation and the induction of a senescent phenotype. These results provide a significant correlation between Id4 expression and AR activity during prostate cancer progression. Loss of AR activity through Id4 promoter hypermethylation may play a crucial role in understanding castration resistant prostate cancer. Therefore, induction of Id4 may provide a novel therapeutic target for advanced stage prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3927. doi:1538-7445.AM2012-3927