The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter analysis revealed that 382 out of 1,188 genes contained cis-acting AR-binding sequences. Chromatin immunoprecipitation confirmed STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A,1 and PIK3CB genes as novel AR targets in PCa disparities. Moreover, functional screens revealed that androgen-stimulated AR binding and upregulation of RHOA, ITGB5, and PIK3CB genes were associated with increased invasive activity of AA PCa cells, as siRNA-mediated knockdown of each gene caused a loss of androgen-stimulated invasion. In summation, our findings demonstrate that transcriptional changes have preferentially occurred in multiple signaling pathways converging (“transcriptional convergence”) on AR signaling, thereby contributing to AR-target gene activation and PCa aggressiveness in AAs. 1. Introduction Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer and, after lung and bronchus cancers, the second leading cause of cancer deaths among American men [1, 2]. In the United States, it is estimated that 241,740 men will be newly diagnosed with prostate cancer, and 28,170 will succumb to this disease in 2012 (http://www.cancer.gov/cancertopics/types/prostate). The human androgen receptor (AR) plays a critical role in the growth and differentiation of the normal prostate gland as well as in the development of PCa [3, 4]. AR expression has been observed in nearly all primary PCa cases [5–7]. Previous studies have also shown that the cellular AR levels are correlated to primary and metastatic lesions and associated with disease progression to castration-resistant PCa (CRPCa) [8–10]. In the US, the African American (AA) population exhibits higher incidence and mortality rates of PCa compared to the Caucasian American (CA) population [11]. Accumulating evidence has suggested that biological factors may in part play a critical role in PCa health disparities that
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