CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells
CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells
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CDK20与KEAP1相互作用激活NRF2并促进肺癌细胞的放化疗耐药
DOI：
10.1038/onc.2017.161
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发表时间：
2017-09-14
期刊：
影响因子：
8
通讯作者：
Xu, S.
中科院分区：
文献类型：
--
作者：
Wang, Q.;Ma, J.;Xu, S.
放化疗耐药被认为是肺癌局部复发和远处转移的主要原因。然而，放射化学抗性的潜在机制仍有待发现。在本研究中，我们确定细胞周期相关激酶（CDK 20）在放化抵抗中的作用。CDK 20是一种新发现的蛋白激酶，在几种癌症的细胞生长和增殖中起着关键作用。使用串联亲和纯化技术，我们提供的证据表明，CDK 20结合泛素连接酶Kelch样ECH相关蛋白1（KEAP 1），其靶向转录因子核因子红细胞2相关因子2（NRF 2）的降解。我们表明，这种相互作用是介导的CDK 20上的进化保守的ETGE基序。此外，我们证明，CDK 20与NRF 2竞争KEAP 1结合，增强NRF 2的转录活性，降低细胞活性氧水平。此外，CDK 20-耗尽的细胞显示受损的细胞增殖，缺陷的G2/M期阻滞和增加的放射化学敏感性在肺癌中。CDK 20敲低诱导的这些表型部分依赖于NRF 2失活。更重要的是，CDK 20在人肺癌组织中过表达，如通过免疫染色所确定的。总的来说，我们的研究结果表明，CDK 20积极调节KEAP 1-NRF 2细胞保护途径，以调节肿瘤的进展和放射化学抗性，这意味着CDK 20是一个新的，有前途的治疗肺癌的靶点。
Radiochemoresistance is considered the main cause of local recurrence and distant metastasis in lung cancer. However, the underlying mechanisms of radiochemoresistance remain to be uncovered. In this study, we determine the functions of cell cycle-related kinase (CDK20) in radiochemoresistance. CDK20 is a newly identified protein kinase, which plays critical roles in cell growth and proliferation in several types of cancer. Using tandem affinity purification technology, we provide evidences that CDK20 binds to the ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1), which targets transcriptional factor nuclear factor erythroid-2-related factor 2 (NRF2) for degradation. We show that this interaction is mediated by an evolutionarily conserved ETGE motif on CDK20. Furthermore, we demonstrate that CDK20 competes with NRF2 for KEAP1 binding, enhances the transcriptional activity of NRF2 and lowers the cellular reactive oxygen species level. Moreover, CDK20-depleted cells display impaired cell proliferation, defective G2/M arrest and increased radiochemosensitivity in lung cancer. These phenotypes induced by CDK20 knockdown are partially dependent on NRF2 inactivation. More importantly, CDK20 is overexpressed in human lung cancer tissues, as determined by immunostaining. Collectively, our results suggest that CDK20 positively modulate the KEAP1–NRF2 cytoprotective pathway to regulate tumor progression and radiochemoresistance, implying that CDK20 is a novel, promising therapeutic target for lung cancer.