Abstract A21: The role of SOX4 in epithelial to mesenchymal transition in prostate cancer

Prostate cancer remains the most commonly diagnosed cancer in U.S. males, and ranks second in mortality with over 28,000 deaths per year. Prostate cancer mortality is typically due to metastases, necessitating the understanding of how metastatic disease develops. One major step for cancer cells to metastasize and acquire migratory and invasive capabilities is the epithelial to mesenchymal transition (EMT). EMT encompasses vast molecular changes in gene expression, mediated by aberrant developmental signaling pathway activation, leading to the loss of cell-cell junctions and planar and apical-basal polarity, increased motility, and resistance to apoptosis and anoikis (cell death due to the detachment from the extracellular matrix). The sex determining region Y-box 4 (SOX4) gene is a developmental transcription factor that is over expressed in prostate cancer and plays a critical role in many developmental pathways inappropriately activated during EMT, such as the transforming growth factor (TGF-beta) and epidermal growth factor receptor (EGFR) signaling pathways. Our data suggest that concomitant treatment of TGF-beta and EGF induces SOX4, and initiates the EMT program in prostate epithelial cell lines. We also demonstrate that SOX4 over expression is sufficient to induce EMT in prostate epithelial cell lines. Currently, the molecular mechanisms that govern how SOX4 initiates EMT via transcriptional activation of target genes are poorly understood. We identified candidate SOX4 targets using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE) on 9755 Pan Cancer samples from The Cancer Genome Atlas (TCGA). Gene ontology analysis of the top 1000 candidate SOX4 targets revealed genes that were enriched for epigenetic processes such as chromatin modification and DNA methylation. One putative target gene, PCAF, is a subunit of a large histone acetyltransferase (HAT) complex. Interestingly, our preliminary data also suggest that SOX4 interacts not only with PCAF, but also with TRRAP, another subunit of the PCAF HAT complex. These data suggest that SOX4 may induce and recruit the PCAF/TRRAP HAT complex in order to transcriptionally activate downstream targets to initiate the EMT program. Citation Format: Nitya V. Sharma, Soma Sannigrahi, YuHeng Lai, Carlos Moreno. The role of SOX4 in epithelial to mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A21.