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

• Published in: The Journal of clinical investigation Vol. 123; no. 7; pp. 2921 - 2934
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2013
• Subjects: 3' Untranslated Regions; Animals; Base Sequence; Binding Sites; Biomedical research; Cancer; Carbon; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - mortality; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic - metabolism; Citric Acid Cycle; Confidence intervals; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Genotype & phenotype; Glucose; Glucose - metabolism; Humans; Labeling; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Metabolism; Mice; Mice, Nude; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Transplantation; NF-E2-Related Factor 2 - physiology; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Oxidative stress; Physiological aspects; RNA Interference; RNA sequencing; Transcription factors; Transcriptome; Tumor Burden; Tumors; United States
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI66353

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.