otic genes, including KIF11, AURKB, and TPX2, are key c-Myc target genes. AR RNAi recapitulated the effect of c-Myc RNAi and also reduced expression of these genes. This demonstrates that AR suppression disrupts c-Myc function and expression of well-established c-Myc target 17689526 genes. Discussion It is well-appreciated that the AR is a critical driver of prostate cancer cell survival and that AR accounts for progression to fatal CRPC despite treatment with ADT. In many cases androgens persist intracellularly within CRPC A-83-01 tumors despite castrate serum levels of androgens. However, androgen ligand-independent but AR-dependent mechanisms that also promote survival of CRPC cells have been reported. These include activation of the AR by IL-6, AR gene amplification, and AR transcript variants that lack the androgen 9570468 ligand binding domain. All of these mechanisms may contribute to prostate cancer progression despite ADT since none are directly targeted by ADT. Recently, it was demonstrated that the AR protein promotes the expression of a gene program distinct from its canonical androgen ligand-directed targets in CRPC cells. One such example is the AR target gene UBE2C that promotes ligand-independent prostate cancer proliferation. Which of the other AR-induced gene products is critical for ligand-independent prostate cancer cell AR and c-Myc Promote Prostate Cancer Progression survival has been unclear. Our work demonstrates that the c-Myc oncogene is such a ligand-independent AR target gene. c-Myc is commonly upregulated in prostate cancer, and c-Myc overexpression transforms normal prostatic epithelial cells in genetically engineered mouse models of prostate cancer and confers ligand-independent prostate cancer cell survival, but the dependency of c-Myc expression on the AR was unclear. We show here that AR and c-Myc are commonly upregulated in CRPC, and we confirmed that AR and c-Myc upregulation strongly correlated with each other in a large series of metastatic CRPC patient tumors. We confirmed that AR suppression leads to loss of c-Myc expression in prostate cancer cell lines expressing full-length AR and in another CRPC cell line 22RV1 that expresses both full-length AR and an AR transcript variant. Although we cannot exclude a role for the AR transcript variant in also promoting c-Myc expression, our results with AR RNAi in LNCaP and Abl and our results with AR overexpression in M12 cells demonstrate that full-length AR is capable of activating c-Myc expression. Like AR RNAi, c-Myc RNAi reduced prostate cancer cell survival in androgen ligand-depleted conditions while co-suppression of AR and c-Myc was not more effective than suppression of either protein alone. 
c-Myc overexpression confers ligand-independent survival to prostate cancer cells, which matches a prior report. We also showed that c-Myc overexpression attenuated the anti-tumor activity of AR suppression with RNAi. Thus, c-Myc contributes to AR’s effects on promoting ligand-independent prostate cancer cell survival. 4 AR and c-Myc Promote Prostate Cancer Progression Despite the fact that AR promotes expression of c-Myc, treatment with androgen ligand did not increase c-Myc expression. Additionally, treatment with androgen ligands did not enhance AR occupancy at the c-Myc enhancer. This contrasts with the effects of androgen stimulation on expression of the KLK3 gene, a well-described androgen-activated gene, and AR occupancy at the KLK3 enhancer. To further confirm that AR promote