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β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells

1
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
2
Japan Society for the Promotion of Science, Tokyo 102-0083, Japan
3
Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Chiba 260-8717, Japan
4
Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
5
Laboratory for Genetic Code, Department of Life and Medical Sciences, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
6
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, and Department of Life and Medical Sciences, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan
*
Author to whom correspondence should be addressed.
These authors contribute equally to this work.
Int. J. Mol. Sci. 2019, 20(13), 3344; https://doi.org/10.3390/ijms20133344
Received: 14 April 2019 / Revised: 2 July 2019 / Accepted: 3 July 2019 / Published: 8 July 2019
(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)
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Abstract

Remarkable upregulation of the NRF2 (NFE2L2)-related transcription factor NRF3 (NFE2L3) in several cancer tissues and its correlation with poor prognosis strongly suggest the physiological function of NRF3 in tumors. Indeed, we had recently uncovered the function of NRF3, which promotes cancer cell proliferation by p53 degradation via the 20S proteasome. Nevertheless, the molecular mechanism underlying the induction of NRF3 gene expression in cancer cells is highly elusive. We herein describe that NRF3 upregulation is induced by the β-catenin/TCF4 complex in colon cancer cells. We first confirmed high NRF3 mRNA expression in human colon cancer specimens. The genome database indicated that the human NRF3 gene possesses a species-conserved WRE sequence (TCF/LEF consensus element), implying that the β-catenin/TCF complex activates NRF3 expression in colon cancer. Consistently, we observed that the β-catenin/TCF4 complex mediates NRF3 expression by binding directly to the WRE site. Furthermore, inducing NRF3 activates cell proliferation and the expression of the glucose transporter GLUT1. The existence of the β-catenin/TCF4-NRF3 axis was also validated in the intestine and organoids of Apc-deficient mice. Finally, the positive correlation between NRF3 and β-catenin target gene expression strongly supports our conclusion. Our findings clearly demonstrate that NRF3 induction in cancer cells is controlled by the Wnt/β-catenin pathway. View Full-Text
Keywords: NRF3; NRF2; β-catenin; Wnt signaling; GLUT1; transcription; colorectal cancer; organoid NRF3; NRF2; β-catenin; Wnt signaling; GLUT1; transcription; colorectal cancer; organoid
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Aono, S.; Hatanaka, A.; Hatanaka, A.; Gao, Y.; Hippo, Y.; Taketo, M.M.; Waku, T.; Kobayashi, A. β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells. Int. J. Mol. Sci. 2019, 20, 3344.

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