Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis
Anju Singh, Christine Happel, Soumen K. Manna, George Acquaah-Mensah, Julian Carrerero, Sarvesh Kumar, Poonam Nasipuri, Kristopher W. Krausz, Nobunao Wakabayashi, Ruby Dewi, Laszlo G. Boros, Frank J. Gonzalez, Edward Gabrielson, Kwok K. Wong, Geoffrey Girnun, Shyam Biswal
Anju Singh, Christine Happel, Soumen K. Manna, George Acquaah-Mensah, Julian Carrerero, Sarvesh Kumar, Poonam Nasipuri, Kristopher W. Krausz, Nobunao Wakabayashi, Ruby Dewi, Laszlo G. Boros, Frank J. Gonzalez, Edward Gabrielson, Kwok K. Wong, Geoffrey Girnun, Shyam Biswal
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Research Article Oncology

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

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

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Figure 8

An autoregulatory loop involving NRF2, HDAC4, and miR-1/206 regulates glucose metabolism.

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An autoregulatory loop involving NRF2, HDAC4, and miR-1/206 regulates gl...
(A) A genetic model showing NRF2-dependent regulation of metabolic gene expression. The effect of NRF2 on glucose metabolism is partly mediated via miR-1 and miR-206. A redox-sensitive HDAC, HDAC4, regulates the transcription of miR-1 and miR-206. HDAC4, with cysteines in a reduced state, accumulates in the nucleus and suppresses miR-1 and miR-206 gene expression. Oxidation of cysteines in HDAC4 results in nuclear export and induces the expression of miR-1 and miR-206. (B) A549 cells harboring a KEAP1 mutation show increased glucose oxidation in the pentose cycle, with increased nucleic acid synthesis, high TCA cycle flux, and de novo fatty acid synthesis. Inhibition of NRF2 activity in KEAP1-deficient A549 cells decreases glucose oxidation in the pentose cycle, with low TCA cycle flux and de novo fatty acid synthesis. Solid arrows indicate activation, and hollow allows indicate inhibition. G6P, glucose-6-P; 3PG, 3-phosphoglyceric acid; Pyr, pyruvate; Lac, lactate.