A Short Biography:

The long-term goal of Dr. Zhou is to seek a better understanding of the tumor biology of pancreatic cancer (PC), the fourth leading cause of cancer deaths in the US, and an effective therapy for this deadly disease. In particular, he is interested in developing pathway-specific small molecule inhibitor(s) of pancreatic and duodenal homeobox-1 (PDX-1) for PC. Dr. Zhou's recent studies have strongly indicated that PDX-1 plays an important role in pancreatic tumorigenesis and a promising therapeutic target. However, whole-body ablation of PDX-1 predictably results in glycemia due to the role for PDX-1 in regulation of insulin expression, thus prompted to identify specific host factors involved in regulation of PDX-1 expression in the context of PC. This proposal is to study the role of protein phosphatase 4 (PP4) in proteolytic control of PDX-1 and PDX-1-mediated pancreatic tumorigenesis based on our preliminary studies that PP4 interacted with and down-regulated PDX-1 with enhanced ubiquitination. His hypothesis is that PP4 is a PDX-1 phosphatase which negatively regulates PDX-1 expression through enhancing a specific E3 ligase-mediated ubiquitination of PDX-1, thus exerting a tumor suppressive effect on pancreatic tumorigenesis. Dr. Zhou proposes to pursue the following specific aims: Aim 1 is to determine if: 1) PP4 is a bona fide PDX-1 phosphatase targeting PDX-1 Ser 269 and 2) PP4 differentially regulates PDX-1 ubiquitination by different E3 ligases. Aim 2 is to determine if: 1) PP4 overexpression inhibits, while PP4 knockdown accelerates, PDX-1-mediated pancreatic tumorigenesis and 2) PP4 is downexpressed in PC. Completion of the proposed studies will lead to the identification of PP4 as the first PDX-1 phosphatase and the E3 ligase(s) responsible for PP4-involved negative regulation of PDX-1 expression, thus providing for a potential targeting therapy for PC treatment. Since aberrant overexpression of PDX-1 is also found in other cancers, our studies will benefit diagnosis, prevention and treatment of other human cancers besides PC. Dr. Zhou is a CURE Pilot and Feasibility recipient.