Steroid receptor coactivators/p160 (SRC) are frequently amplified and overexpressed in various human cancers which mediate transcriptional functions of nuclear receptors and other transcription factors, providing survival advantage to cancer cells. Recent findings from genomic profiling of human prostate tumors have identified SRC-2 (also known as NCOA2/TIF2), one of the SRC family member as the major oncogene. SRC-2 was found to be significantly enhanced in 8% of primary tumors and 37% of metastatic tumors, and its expression positively correlated with disease recurrence. This suggests SRC-2 oncogene may play crucial role in the development and metastatic progression of prostate cancer. The current study is aimed to understand the molecular function of SRC-2 in the pathogenesis of prostate cancer. RNAi mediated knockdown of SRC-2 in cultured prostate cancer cell lines significantly reduced the cell viability and this phenotype was rescued by ectopic overexpression of SRC-2. Since SRC-2 coactivator is a master regulator of key metabolic pathways in normal cellular physiology, we investigated its role in cancer cell metabolism. Depletion of SRC-2 severely impairs accumulation of lipid droplets, suggesting SRC-2 regulates lipogenesis in cancer cells. Lipid biosynthetic pathways are integral part of cancer cell growth generating fatty acids and cholesterol required for the biogenesis of membrane. Lipids derive majority of carbon chain from glucose flux by diverting pyruvate into acetyl coenzyme A, an important precursor for lipid biosynthesis. Initial screening identified SRC-2 regulates expression of key metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), pyruvate dehydrogenase (PDH), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD1) involved in fatty acid and cholesterol biosynthesis. Interestingly we found expression of HMGCR, FASN and PDH is dramatically increased in metastatic C4-2 cells compared to parental LNCaP cells, and their expression can be reversed by SRC-2 depletion. Ongoing studies will further examine the regulation of glucose and pyruvate metabolism by SRC-2 and its importance in cancer cell metastasis. Although it is well known that many tumours exhibit increased glycolysis, less clear is how associated metabolic pathways are affected and whether they contribute to cancer cell proliferation. These analyses will allow us to identify unpredictable nodes of metabolic regulation by SRC-2 oncogene and may provide rational treatment approaches for targeting tumor metabolism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5153. doi:1538-7445.AM2012-5153