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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2921-2934
Number of pages14
JournalJournal of Clinical Investigation
Volume123
Issue number7
DOIs
StatePublished - Jul 1 2013

Fingerprint

NF-E2 Transcription Factor
Pentose Phosphate Pathway
Carcinogenesis
MicroRNAs
Neoplasms
Gene Expression
Carbon Cycle
Glucose
Histone Deacetylases
Ribose
Citric Acid Cycle
Genomics
NADP
Genes
Oxidation-Reduction
Homeostasis
Cell Proliferation
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 123, No. 7, 01.07.2013, p. 2921-2934.

Research output: Contribution to journalArticle

Singh, A, Happel, C, Manna, SK, Acquaah-Mensah, G, Carrerero, J, Kumar, S, Nasipuri, P, Krausz, KW, Wakabayashi, N, Dewi, R, Boros, LG, Gonzalez, FJ, Gabrielson, E, Wong, KK, Girnun, G & Biswal, S 2013, 'Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis', Journal of Clinical Investigation, vol. 123, no. 7, pp. 2921-2934. https://doi.org/10.1172/JCI66353
Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. Journal of Clinical Investigation. 2013 Jul 1;123(7):2921-2934. https://doi.org/10.1172/JCI66353
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. / Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 7. pp. 2921-2934.
@article{5b81e34f51bd4b2783f6db612f63e943,
title = "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.",
author = "Anju Singh and Christine Happel and Manna, {Soumen K.} and George Acquaah-Mensah and Julian Carrerero and Sarvesh Kumar and Poonam Nasipuri and Krausz, {Kristopher W.} and Nobunao Wakabayashi and Ruby Dewi and Boros, {Laszlo G.} and Gonzalez, {Frank J.} and Edward Gabrielson and Wong, {Kwok K.} and Geoffrey Girnun and Shyam Biswal",
year = "2013",
month = "7",
day = "1",
doi = "10.1172/JCI66353",
language = "English (US)",
volume = "123",
pages = "2921--2934",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

TY - JOUR

T1 - Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis

AU - Singh, Anju

AU - Happel, Christine

AU - Manna, Soumen K.

AU - Acquaah-Mensah, George

AU - Carrerero, Julian

AU - Kumar, Sarvesh

AU - Nasipuri, Poonam

AU - Krausz, Kristopher W.

AU - Wakabayashi, Nobunao

AU - Dewi, Ruby

AU - Boros, Laszlo G.

AU - Gonzalez, Frank J.

AU - Gabrielson, Edward

AU - Wong, Kwok K.

AU - Girnun, Geoffrey

AU - Biswal, Shyam

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84879661552&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879661552&partnerID=8YFLogxK

U2 - 10.1172/JCI66353

DO - 10.1172/JCI66353

M3 - Article

VL - 123

SP - 2921

EP - 2934

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -