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

被引：33

作者：

Aono, Shiori ^{[1
]}

Hatanaka, Ayari ^{[1
]}

Hatanaka, Atsushi ^{[1
,2
]}

Gao, Yue ^{[1
]}

Hippo, Yoshitaka ^{[3
]}

Taketo, Makoto Mark ^{[4
]}

Waku, Tsuyoshi ^{[5
]}

Kobayashi, Akira ^{[6
,7
]}

机构：

[1] Doshisha Univ, Grad Sch Life & Med Sci, Lab Genet Code, Kyoto 6100394, Japan

[2] Japan Soc Promot Sci, Tokyo 1020083, Japan

[3] Chiba Canc Ctr, Res Inst, Div Mol Carcinogenesis, Chiba, Chiba 2608717, Japan

[4] Kyoto Univ, Grad Sch Med, Div Expt Therapeut, Kyoto 6068501, Japan

[5] Doshisha Univ, Fac Life & Med Sci, Dept Life & Med Sci, Lab Genet Code, Kyoto 6100394, Japan

[6] Doshisha Univ, Fac Life & Med Sci, Grad Sch Life & Med Sci, Lab Genet Code, Kyoto 6100394, Japan

[7] Doshisha Univ, Fac Life & Med Sci, Dept Life & Med Sci, Kyoto 6100394, Japan

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2019年 / 20卷 / 13期

关键词：

NRF3; NRF2; beta-catenin; Wnt signaling; GLUT1; transcription; colorectal cancer; organoid; BETA-CATENIN; DISEASE; EXPRESSION; SCREEN; COLON;

D O I：

10.3390/ijms20133344

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta-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 beta-catenin/TCF complex activates NRF3 expression in colon cancer. Consistently, we observed that the beta-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 beta-catenin/TCF4-NRF3 axis was also validated in the intestine and organoids of Apc-deficient mice. Finally, the positive correlation between NRF3 and beta-catenin target gene expression strongly supports our conclusion. Our findings clearly demonstrate that NRF3 induction in cancer cells is controlled by the Wnt/beta-catenin pathway.

引用

页数：15

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