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CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells
1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
Cell cycle-related kinase 20 (CDK20) enhances lung cancer
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Radiochemoresistance drives lung cancer recurrence and metastasis.
- Mechanisms underlying radiochemoresistance are not fully understood.
- Cell cycle-related kinase 20 (CDK20) is implicated in cancer cell growth.
Purpose of the Study:
- To investigate the role of CDK20 in lung cancer radiochemoresistance.
- To elucidate the molecular mechanisms by which CDK20 influences radiochemoresistance.
Main Methods:
- Tandem affinity purification to identify CDK20 interacting proteins.
- Immunostaining to assess CDK20 expression in lung cancer tissues.
- Cell proliferation assays, G2/M arrest analysis, and radiochemosensitivity testing following CDK20 depletion.
Main Results:
- CDK20 binds to Kelch-like ECH-associated protein 1 (KEAP1), a regulator of nuclear factor erythroid-2-related factor 2 (NRF2).
- CDK20 enhances NRF2 transcriptional activity, reduces reactive oxygen species, and promotes cell proliferation and G2/M arrest.
- CDK20 depletion increases lung cancer cell sensitivity to radiochemotherapy, partly via NRF2 inactivation.
- CDK20 is overexpressed in human lung cancer tissues.
Conclusions:
- CDK20 promotes lung cancer progression and radiochemoresistance by modulating the KEAP1-NRF2 pathway.
- CDK20 represents a potential therapeutic target for overcoming lung cancer radiochemoresistance.
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