A long noncoding RNA connects c-Myc to tumor metabolism

Chiu Lien Hung, Ling Yu Wang, Yen Ling Yu, Hongwu Chen, Shiv Srivastava, Gyorgy Petrovics, Hsing-Jien Kung

Research output: Contribution to journalArticle

140 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)18697-18702
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number52
DOIs
StatePublished - Dec 30 2014

Fingerprint

Long Noncoding RNA
Neoplasm Genes
Prostatic Neoplasms
Gene Expression
Neoplasms
Androgen Receptors
Pentose Phosphate Pathway
Metabolic Networks and Pathways
Androgens
Prostate
Nucleotides
Physiological Phenomena
Glucose
Citric Acid Cycle
Glycolysis
Pathologic Processes
Glutamine
NADP
Transcriptional Activation
Chromatin

Keywords

  • C-Myc coactivator
  • LncRNA
  • Prostate cancer
  • Tumor metabolism

ASJC Scopus subject areas

  • General

Cite this

A long noncoding RNA connects c-Myc to tumor metabolism. / Hung, Chiu Lien; Wang, Ling Yu; Yu, Yen Ling; Chen, Hongwu; Srivastava, Shiv; Petrovics, Gyorgy; Kung, Hsing-Jien.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 52, 30.12.2014, p. 18697-18702.

Research output: Contribution to journalArticle

Hung, Chiu Lien ; Wang, Ling Yu ; Yu, Yen Ling ; Chen, Hongwu ; Srivastava, Shiv ; Petrovics, Gyorgy ; Kung, Hsing-Jien. / A long noncoding RNA connects c-Myc to tumor metabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 52. pp. 18697-18702.
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