Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis.
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.
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA. asingh1@jhsph.edu
Anju
A
Singh
Christine
C
Happel
Soumen K
SK
Manna
George
G
Acquaah-Mensah
Julian
J
Carrerero
Sarvesh
S
Kumar
Poonam
P
Nasipuri
Kristopher W
KW
Krausz
Nobunao
N
Wakabayashi
Ruby
R
Dewi
Laszlo G
LG
Boros
Frank J
FJ
Gonzalez
Edward
E
Gabrielson
Kwok K
KK
Wong
Geoffrey
G
Girnun
Shyam
S
Biswal
D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002952:Citric Acid Cycle; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D034622:RNA Interference; D059467:Transcriptome; D047368:Tumor Burden
D020413:3' Untranslated Regions; C544547:MIRN1 microRNA, human; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005947:Glucose