Abstract B16: A novel long non-coding RNA connects c-Myc to tumor metabolism

Abstract

Abstract Long non-coding RNAs have been implicated in a variety of physiological and pathological processes including cancer. In prostate cancer, PCGEM1 (prostate cancer gene expression marker 1) is an androgen-induced prostate specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential was recently shown to be in part due to its ability to activate androgen receptor (AR). Here we report a novel function of PCGEM1 that provides growth advantages for cancer cell by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at the transcriptional level that affects multiple metabolic pathways including glucose and glutamine metabolism, pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and TCA cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified c-Myc binding domain on PCGEM1 that contributes to the PCGEM1 dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cell. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor specific way, making it a promising target for therapeutic intervention. Citation Format: Ling-Yu Wang, Chiu-Lien Hung, Yen-Ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing-Jien Kung. A novel long non-coding RNA connects c-Myc to tumor metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B16.