NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor
NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor
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DOI：
10.1016/j.celrep.2019.09.087
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发表时间：
2019-11-05
期刊：
影响因子：
8.8
通讯作者：
Blank, Volker
中科院分区：
文献类型：
--
作者：
Bury, Marina;Le Calve, Benjamin;Blank, Volker
组成性核因子κ B（NF-κ B）活化是结肠肿瘤生长的标志。细胞周期蛋白依赖性激酶（CDK）是重要的细胞周期调节因子，抑制CDK活性已成功地用于抗癌治疗。在这里，我们表明，NFE 2 L3转录因子的功能作为一个关键的调节剂的途径，连接NF-κ B B信号的CDK 1活性的控制，从而驱动结肠癌细胞增殖。我们发现NFE 2 L3的表达受NF-κ B B的RELA亚基的调节，并且与正常邻近组织相比，结肠腺癌患者的NFE 2 L3水平升高。NFE 2L 3的沉默显著降低体外结肠癌细胞增殖和体内肿瘤生长。NFE 2L 3敲低导致双同源框因子4（DUX 4）水平增加，DUX 4作为CDK 1的直接抑制剂发挥作用。发现的控制细胞周期进程的致癌途径可能为精确的癌症治疗开辟独特的途径。
Constitutive nuclear factor kappa B (NF-kappa B) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-kappa B signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-kappa B and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.