Potential Role for Nuclear Matrix Proteins Hnrnph1 and SAFB-2 in Ethnic Disparity of Prostate Cancer

B99 The underlying role of genomic alterations in the disproportionate incidence and mortality of prostate cancer (CaP) in African Americans (AA) as opposed to Caucasians (CS) are not well understood. We, for the first time, identified a CaP genes that are differentially expressed in CaP cells of age-(50-60 years) and tumor grade-matched (Gleason score 6) AA and CS patients. Race-based CaP specific cDNAs were enriched by suppressive subtractive hybridization (SSH) analysis on in vivo -derived genetic material originating from flash-frozen specimen. The cDNA SSH libraries were used to construct two unique sets of microarray chips with ~750 CaP genes for each race group. Using microarray, DNA sequencing, qPCR and IHC analyses on biopsies of large cohort of patients we identified selective upregulation (~ 90%) of nuclear matrix genes, heterogeneous nuclear ribonucleoprotein H1 (hnRNP-H1) and scaffold attachment factor B2 (SAFB-2), in CaP cells of AA men. The proteins were found to be constitutively expressed in AA-derived MDA-CaP-2b cells, but not the CS-derived LNCaP or PC-3 cells, and that their siRNA silencing inhibited growth of MDA-PCa-2b cells only. Hyperacetylation by HDAC inhibitor hn380 increases expression of hnRNPH1 in MDA-PCa-2b cells, suggesting an epigenetic mechanism is selectively involved in upregulating this gene in CaP cells of AA men. Co-IP and reporter assays demonstrate that hnRNP-H1 protein binds to and transactivates androgen receptor (AR) in a ligand-independent manner in both MDA-PCa-2b and COS-7 cells. Intriguingly, hnRNPH1 induces an additive or synergistic induction of androgen-induced AR transactivation in these cells. Our results suggest that overexpression of nuclear matrix proteins may stimulate prostate tumor growth in part by activating AR target genes in AA men. Our studies suggest differences in the biology of CaP may account in part for ethnic disparity of disease morbidity and mortality and further identified a potential target to circumvent the disease in AA men.