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CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells

Oncogene volume 36, pages 5321–5330 (2017)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81301719 to SX), Open Funds of State Key Laboratory of Oncology in South China (HN2014-10 to SX), a grant from the Wuhan Science and Technology Bureau (2015060101010041 to SX), the National Natural Science Foundation of China (81372435 to KY) and Department of Defense Era of Hope research scholar award (W81XWH-09-1-0409 to JC).

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Author notes

  1. Q Wang and J Ma: These two authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Q Wang, J Ma, Y Lu, S Zhang, J Huang, J Chen, K Yang, G Wu & S Xu

  2. Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China

    J-X Bei

  3. Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    K Huang

  4. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    K Huang

  5. Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    J Chen

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Wang, Q., Ma, J., Lu, Y. et al. CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells. Oncogene 36, 5321–5330 (2017). https://doi.org/10.1038/onc.2017.161

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