Androgen receptor and prostate apoptosis response factor-4 target the c-FLIP gene to determine survival and apoptosis in the prostate gland

Androgen receptor (AR) is a ligand-activated transcription factor that mediates the action of androgens and is essential for the growth, function, and cell differentiation of the prostate gland. Here, we demonstrated that the prostate apoptosis response factor-4 (par-4) functions as a novel AIR coactivator. Par-4 physically interacted with the DNA-binding domain of AR, enhanced AIR interaction with DNA, and increased AR-dependent transcription. Par-4 enhanced the c-FLIP promoter activity and was recruited on to the c-FLIP gene in the presence of androgens, and the dominant-negative par-4 decreased c-FLIP expression. These results suggest that, in addition to its proapoptortic function, par-4 acts as a novel transcription cofactor for AIR to target c-FLIP gene expression. In addition, we demonstrated that loss of c-FLIP expression was essential for castration-induced apoptosis in the prostate gland and that enhanced c-FLIP expression was associated with prostate cancer progression to the androgen-resistant stage. Our data shed light on a transcription-mediated mechanism for the effects of the AIR pathway on cell survival and apoptosis.