PROJECT SUMMARY Prostate cancer is the second leading cause of cancer-related deaths among men in the United States. African- American men have the highest incidence and mortality rate compared to any other race. Metastatic prostate cancer particularly to the bones is the major cause of mortalities from this disease. The cellular and molecular mechanisms that contribute to metastatic prostate cancer remains poorly understood, obstructing the development of an effective therapy that improves the quality of life of patients with metastatic disease. The primary goal of this research will be to investigate whether the transcriptional coactivator YAP/TAZ and the nuclear factor Kappa B (NFκB) subunit RELA transcription factor functionally interact to contribute to human prostate cancer with invasive characteristics. Ongoing clinical and preclinical studies suggest that increases in nuclear YAP and RELA activity correlates in aggressive prostate cancer. In addition, stromal-cell derived factors such as SDF1α, a potent promoter of cancer metastasis, enhanced the interaction between native YAP and RELA proteins in the cell. Moreover, the Hippo-like protein kinase STK4, a potent inhibitor of YAP activity, attenuated the activation of the NFκB responsive reporter gene. Furthermore, computational analysis revealed that the YAP and NFκB co-might regulate several oncogenes that are associated with poor cancer prognosis. These observations support the overarching hypothesis that increases in nuclear YAP and RELA activity and interaction enhance prostate cancer cell migration and metastasis though the YAP-mediated alterations of the NFκB transcriptional programs in the cell. The primary objectives of this research are to demonstrate (a) whether increases in nuclear YAP and RELA expression correlate with high grade and metastatic human prostate cancer, (b) to demonstrate whether YAP is required for RELA-mediated prostate cancer cell migration and metastasis, and (c) to demonstrate whether YAP functions as a key mediator of the NFκB gene transcriptions that overlap with prostate cancer cell migration and metastasis. It is anticipated that this study will provide important mechanistic insights into the functional and molecular interactions between the YAP/TAZ and NFκB pathways in regulating cell migration and metastasis. Thus, deeper understanding the molecular pathway in prostate progression and metastasis could benefit patient care through improved disease surveillance and selection of patients for more effective therapy, which may reduce disparities in prostate cancer mortality. In addition, the concept to be tested via this research can be applied to other cancers because YAP and NFκB play a critical role in the etiology of many cancers with poor outcomes.