title: A long noncoding RNA connects c-Myc to tumor metabolism.
abstract: Long noncoding RNAs (lncRNAs) 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 lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic 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 glutamine 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.
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817;
authors.forename: Chiu-Lien
authors.initials: CL
authors.lastname: Hung
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817;
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Wang
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan; and.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817;
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
authors.forename: Shiv
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California at Davis, Sacramento, CA 95817; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan; and hkung@ucdavis.edu.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000332:Aerobiosis / Q000235:genetics; D045744:Cell Line, Tumor; D006019:Glycolysis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009249:NADP / Q000235:genetics / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000235:genetics; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
chemical_list: C489427:MYC protein, human; C416084:PCGEM1 non-coding RNA, human; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; D011944:Receptors, Androgen; D009249:NADP
keywords: c-Myc coactivator; lncRNA; prostate cancer; tumor metabolism