β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells
β-Catenin/TCF4 Complex-Mediated Induction of the NRF3 (NFE2L3) Gene in Cancer Cells
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DOI：
10.3390/ijms20133344
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Kobayashi, Akira
中科院分区：
文献类型：
--
作者：
Aono, Shiori;Hatanaka, Ayari;Kobayashi, Akira
NRF 2（NFE 2L 2）相关转录因子NRF 3（NFE 2L 3）在几种癌症组织中的显著上调及其与不良预后的相关性强烈表明NRF 3在肿瘤中的生理功能。事实上，我们最近发现了NRF 3的功能，它通过20 S蛋白酶体降解p53促进癌细胞增殖。然而，在癌细胞中诱导NRF 3基因表达的分子机制是非常难以捉摸的。我们在此描述了NRF 3上调是由结肠癌细胞中的β-连环蛋白/TCF 4复合物诱导的。我们首次证实了NRF 3 mRNA在人结肠癌标本中的高表达。基因组数据库表明，人类NRF 3基因具有物种保守的WRE序列（TCF/LEF共有元件），这意味着β-连环蛋白/TCF复合物激活NRF 3在结肠癌中的表达。因此，我们观察到β-连环蛋白/TCF 4复合物通过直接结合WRE位点介导NRF 3表达。此外，诱导NRF 3激活细胞增殖和葡萄糖转运蛋白GLUT 1的表达。β-连环蛋白/TCF 4-NRF 3轴的存在也在APC缺陷小鼠的肠和类器官中得到验证。最后，NRF 3和β-连环蛋白靶基因表达之间的正相关性强有力地支持了我们的结论。我们的研究结果清楚地表明，癌细胞中的NRF 3诱导是由Wnt/β-连环蛋白途径控制的。
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.