The human positive cofactor 4 promotes androgen-independent prostate cancer development and progression through HIF-1α/β-catenin pathway.

Androgen-dependent prostate cancer (ADPC) eventually progresses to androgen-independent prostate cancer (AIPC), that has a poor prognosis owing to its unclear mechanism and lack of effective therapeutic targets. The human positive cofactor 4 (PC4) is a transcriptional cofactor, and plays a potential role in cancer development. However, the significance and mechanism of PC4 in AIPC progression are unclear. By analyzing the clinical data, we find that PC4 is overexpressed in prostate cancer and closely correlated with the progression, metastasis and prognosis of patients. Additionally, PC4 is significantly upregulated in AIPC cells compared with ADPC cells, implying its importance in the development and progression of AIPC. Then, in vivo and in vitro studies reveal that loss of PC4 inhibits cell growth by suppressing c-Myc/P21 pathway and inducing cell cycle arrest at G1/S phase transition in AIPC. PC4 knockdown also attenuates EMT-mediated metastasis in AIPC. Moreover, for the first time, we find that PC4 exerts its oncogenic functions by promoting the expression of HIF-1α and activating β-catenin signaling. Therefore, our findings determine the signatures and molecular mechanisms of PC4 in AIPC, and indicate that PC4 might be a promising therapeutic target for AIPC.