Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis.

Abstract

The mechanisms by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood. Using an integrated genomics and ¹³C-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 and miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of NRF2 signaling in cancer cells attenuated miR-1 and miR-206 expression, leading to enhanced expression of PPP genes. Conversely, overexpression of miR-1 and miR-206 decreased the expression of metabolic genes and dramatically impaired NADPH production, ribose synthesis, and in vivo tumor growth in mice. Loss of NRF2 decreased the expression of the redox-sensitive histone deacetylase, HDAC4, resulting in increased expression of miR-1 and miR-206, and not only inhibiting PPP expression and activity but functioning as a regulatory feedback loop that repressed HDAC4 expression. In primary tumor samples, the expression of miR-1 and miR-206 was inversely correlated with PPP gene expression, and increased expression of NRF2-dependent genes was associated with poor prognosis. Our results demonstrate that microRNA-dependent (miRNA-dependent) regulation of the PPP via NRF2 and HDAC4 represents a novel link between miRNA regulation, glucose metabolism, and ROS homeostasis in cancer cells.

Authors

Singh, Anju; Happel, Christine; Manna, Soumen K; Acquaah-Mensah, George; Carrerero, Julian; Kumar, Sarvesh; Nasipuri, Poonam; Krausz, Kristopher W; Wakabayashi, Nobunao; Dewi, Ruby; Boros, Laszlo G; Gonzalez, Frank J; Gabrielson, Edward; Wong, Kwok K; Girnun, Geoffrey; Biswal, Shyam;

Keywords

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Binding Sites
  • Carcinoma, Non-Small-Cell Lung/ metabolism
  • Carcinoma, Non-Small-Cell Lung/ mortality
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic/ metabolism
  • Citric Acid Cycle
  • Gene Expression Regulation, Neoplastic
  • Glucose/ metabolism
  • Humans
  • Lung Neoplasms/ metabolism
  • Lung Neoplasms/ mortality
  • Mice
  • Mice, Nude
  • MicroRNAs/ genetics
  • MicroRNAs/ metabolism
  • NF-E2-Related Factor 2/ physiology
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • RNA Interference
  • Transcriptome
  • Tumor Burden

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