Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma.
Loss of Nrf2 abrogates the protective effect of Keap1 downregulation in a preclinical model of cutaneous squamous cell carcinoma.
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DOI：
10.1038/srep25804
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发表时间：
2016-05-24
影响因子：
4.6
通讯作者：
Dinkova-Kostova AT
中科院分区：
文献类型：
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作者：
Knatko EV;Higgins M;Fahey JW;Dinkova-Kostova AT
皮肤鳞状细胞癌（cSCC）是最常见且高度突变的人类恶性肿瘤，对驱动突变的识别和靶向治疗具有挑战性。转录因子 NF-E2 p45 相关因子 2 (Nrf2) 协调细胞保护诱导程序，抵消太阳紫外线辐射的破坏作用，这是 cSCC 发展的主要病因。 Kelch 样 ECH 相关蛋白 1 (Keap1) 是一种 Cullin-3/Rbx1 泛素连接酶底物衔接蛋白，介导 Nrf2 泛素化和蛋白酶体降解，其下调在 cSCC 临床前模型中具有很强的保护作用。然而，除了Nrf2之外，Keap1还影响致癌过程中其他蛋白质的泛素化，包括参与炎症和DNA损伤修复的蛋白质。在这里，我们培育了 Nrf2 被破坏的 Keap1flox/flox SKH-1 无毛小鼠 (Keap1flox/flox/Nrf2−/−)，并将它们长期暴露在模拟太阳的紫外线辐射下。我们发现 Keap1flox/flox/Nrf2−/− 小鼠中形成的 cSCC 的发生率、多重性和负担远大于 Keap1flox/flox/Nrf2+/+ 小鼠，从而确定 Nrf2 激活作为保护介质。我们的研究结果进一步表明，在全球范围内抑制 Nrf2（一种针对癌症治疗提出的策略）不太可能有益。
Cutaneous squamous cell carcinomas (cSCC) are the most common and highly mutated human malignancies, challenging identification of driver mutations and targeted therapies. Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates a cytoprotective inducible program, which counteracts the damaging effects of solar UV radiation, the main etiological factor in cSCC development. Downregulation of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adaptor protein, which mediates the ubiquitination and proteasomal degradation of Nrf2, has a strong protective effect in a preclinical model of cSCC. However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the carcinogenesis process, including proteins involved in inflammation and DNA damage repair. Here, we generated Keap1flox/flox SKH-1 hairless mice in which Nrf2 is disrupted (Keap1flox/flox/Nrf2−/−) and subjected them chronically to solar-simulated UV radiation. We found that the incidence, multiplicity and burden of cSCC that form in Keap1flox/flox/Nrf2−/− mice are much greater than in their Keap1flox/flox/Nrf2+/+ counterparts, establishing Nrf2 activation as the protection mediator. Our findings further imply that inhibition of Nrf2 globally, a strategy proposed for cancer treatment, is unlikely to be beneficial.