Despite numerous strategies for treatment of prostate cancer, there is still shortage in effective approaches of targeting castration resistant prostate cancer (CRPC) and associated mortality. A wide variety of resistance mechanisms has been discovered in CRPC over the last decades. Novel therapeutic targets for CRPC are required. Myristoylation is a co/post-translational protein modification that promote localization of proteins to cellular membranes, thereby maintaining their conformation and molecular functions. A growing body of evidence, including those studies in prostate cancer from our laboratory, has demonstrated that protein myristoylation promotes cancer progression. This dissertation focuses on studies of the role of N-myristoyltransferase 1 (NMT1) in prostate cancer. In the first aim of the study, we determined expression levels and activity of NMT1 and how it impacted growth of the prostate cancer. Our data indicated that NMT1 was highly expressed in prostate cancer cells compared to normal prostate cells. Genetic knockdown of NMT1 inhibited proliferaion of prostate cancer cells through induction of cell cycle arrest. Additionally, we identified a small molecule inhibitor that suppressed NMT1 activity at low micromolar range. Pharmacological inhibition of NMT1 suppressed growth of prostate tumors in vivo. In the second aim of

the study, we investigated a regulatory role of NMT1 on AR protein expression and activity in prostate cancer tumorigenesis. We showed that NMT1 expression levels and activity regulated AR protein levels. Inhibiting NMT1 genetically or pharmacologically reduced AR proteins levels, but not at its mRNA levels. A decrease of AR protein levels was coupled with reduction of nuclear AR levels and its transcriptional activity. We further demonstrated that NMT1 regulated AR protein levels through ubiquitination- proteasome pathway. Finally, our results indicated that NMT1 synergized with AR to promote prostate cancer tumorigenesis. Taken together, our study has discovered a novel molecular function of NMT1 in regulation of AR protein levels in prostate cancer, and a therapeutic approach for treatment of CRPC.