Pilot: Determining the Role of AR-Repressed Gene, CCDC83 in Conferring Anti-Androgen Resistance in Prostate Cancer

Principal Investigator: Fong, Ka-wing (Will) 18.2 2. PROJECT TITLE: Determining the role of AR-repressed gene, CCDC83 in conferring anti- androgen resistance in prostate cancer 3. ABSTRACT: Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer and the second-leading cause of cancer mortality among American men. Androgen receptor (AR) is a hormone-stimulated nuclear receptor and aberrant AR signaling is one of the most important driving forces for PCa progression. The standard treatment for recurrent PCa is androgen-deprivation therapy (ADT), however, a majority of PCa patients develop resistance to ADT and ultimately result in castration-resistant prostate cancer (CRPC). Although the new-generation ADT enzalutamide (Enz), which acts as an antagonist of the AR, has been shown to significantly prolong overall survival for patients with metastatic CRPC, Enz resistance inevitably develops and remains an incurable disease. The mechanism underlying Enz resistance remains yet to be fully understood. Thus, a key to overcoming Enz-resistance is to identify the driver genes of promoting Enz- resistance survival. Our and other studies has demonstrated AR can function as a transcriptional repressor. Interestingly, Enz antagonizes AR activity, which also restore the expression of AR-repressed genes, and their aberrant expression in turn promote Enz-resistant survival through multiple pathways. In our preliminary studies, we found that androgen/AR represses while Enz induces CCDC83 expression. In an unbiased proteomic screen, we identify CCDC83-interacting protein, PFK-1, which is one of the most important regulatory enzymes for glycolysis. Like PFK-1, CCDC83 promotes glycolysis, which is indispensable for Enz-resistant PCa growth. Hence, our central hypothesis is that AR suppress CCDC83 gene expression through repressive epigenetic remodeling and that Enz treatment unleashes the expression of CCDC83 which subsequently interacts with PFK-1 complex to stimulate aerobic glycolysis and to sustain biosynthetic pathway essential for Enz-resistant PCa growth. To test these hypotheses, Aim 1 we will elucidate the mechanism by which AR repress CCDC83 expression. Aim 2 we will dissect the functional significance of CCDC83 interaction with PFK-1 complex during PCa progression. Cancer relevance: Although metastatic CRPC initially responses to Enz treatment, drug-resistance inevitably develops and remains an incurable disease. It’s imperative to identify new targets and develop novel approaches to treat Enz-resistant CRPC. Most cancer cells produce energy predominantly by a high rate of glycolysis, followed by lactic acid fermentation in the cytosol. This metabolic alteration, termed the Warburg effect, provides the high energy and biosynthetic materials required for tumor cell growth. In the glycolytic pathway, phosphofructokinase 1 (PFK1) catalyzes one of the key regulatory and rate-limiting steps of glycolysis. The mechanisms underlying PFK1 activation in cancer cells still need to be elucidated. The results from this proposal will not only advance the fields of cancer metabolism, but also establish CCDC83 as a novel target for drug-resistant CRPC. Institutional Research Grant American Cancer Society – January 2019