TY - JOUR
T1 - CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells
AU - Wang, Q.
AU - Ma, J.
AU - Lu, Y.
AU - Zhang, S.
AU - Huang, J.
AU - Chen, J.
AU - Bei, Jin-Xin
AU - Yang, K.
AU - Wu, G.
AU - Huang, K.
AU - Chen, J.
AU - Xu, S.
N1 - Funding Information:
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).
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/9/14
Y1 - 2017/9/14
N2 - 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 cyclerelated 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.
AB - 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 cyclerelated 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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U2 - 10.1038/onc.2017.161
DO - 10.1038/onc.2017.161
M3 - Article
C2 - 28534518
AN - SCOPUS:85019632543
SN - 0950-9232
VL - 36
SP - 5321
EP - 5330
JO - Oncogene
JF - Oncogene
IS - 37
ER -