A long noncoding RNA connects c-Myc to tumor metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 52; pp. 18697 - 18702
• Main Authors: Hung, Chiu-Lien, Wang, Ling-Yu, Yu, Yen-Ling, Chen, Hong-Wu, Srivastava, Shiv, Petrovics, Gyorgy, Kung, Hsing-Jien
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30-12-2014; National Acad Sciences
• Subjects: Aerobiosis - genetics; Biological Sciences; Cancer; Cell growth; Cell Line, Tumor; Cellular metabolism; Chromatin; Fatty acids; Gene expression regulation; Glycolysis - genetics; HEK293 Cells; Homeostasis; Humans; Lipid metabolism; Male; Metabolism; NADP - genetics; NADP - metabolism; Pentose Phosphate Pathway - genetics; Promoter Regions, Genetic; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Structure, Tertiary; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Tumors; prostate cancer; lncRNA; c-Myc coactivator; tumor metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1415669112

Long noncoding RNAs (IncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific IncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenie potential has been 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 cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and g Iutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid 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 a 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 cells. 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.