Functional interference of androgen receptor signaling by the Inhibitor of Growth 1
The androgen receptor (AR) signaling is critical for prostate cancer (PCa) progression to the castration-resistant stage with poor clinical outcome. Altered function of AR interacting factors contributes to castration-resistant PCa (CRPCa). Inhibitor of growth 1 (ING1) is an epigenetic regulator of various cellular processes including proliferation and cellular senescence. ING1 dysregulation and its signaling have been implicated in PCa, but its role in AR signaling is still unknown. Based on the shown interaction between AR and ING1b, specific targeting the AR by ING1b can be one possible way to inhibit the AR signaling and induce cellular senescence in PCa cells. The results indicate that ING1b expression is downregulated in CRPCa cells compared to androgen-dependent ones. Thereby, its ectopic expression induces cellular senescence and reduces cell migration in both PCa cells. ING1b knockdown (KD) analysis indicates that ING1b is a downstream target of AR-mediated cellular senescence in PC3-AR cells. ING1b overexpression represses AR transactivation on key target genes in LNCaP cells possibly through AR degradation. Intriguingly, ING1b KD inhibits AR-mediated transcriptional regulation of the same target genes in both PCa cells, which could be verified in vivo using Ing1 KO mice. This interesting result could be explained by the compensatory mechanism through enhanced expression of the ING2a protein in ING1-deficient condition as ectopic expression of ING2a also hampers the AR transcriptional activation similar to ING1b. Taken together, this compensatory mechanism suggests a novel crosstalk among ING family members in regulating AR functions and opens a potential way to inhibit AR signaling in PCa.