Theranostics 2018; 8(3):650-662. doi:10.7150/thno.21963

Research Paper

CDK16 Phosphorylates and Degrades p53 to Promote Radioresistance and Predicts Prognosis in Lung Cancer

Jie Xie1*, Yan Li1*, Ke Jiang2*, Kaishun Hu3, Sheng Zhang1, Xiaorong Dong1, Xiaofang Dai1, Li Liu1, Tao Zhang1, Kunyu Yang1, Kai Huang4, Junjie Chen5, Shaojun Shi6, Yu Zhang6, Gang Wu1✉, Shuangbing Xu1✉

1. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
2. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China;
4. Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
5. Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
6. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
* These authors contributed equally to this work

Abstract

Rationale: Radioresistance is considered the main cause of local relapse in lung cancer. However, the molecular mechanisms of radioresistance remain poorly understood. This study investigates the role of CDK16 in radioresistance of human lung cancer cells.

Methods: The expression levels of CDK16 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues. Immunoprecipitation assay and GST pulldown were utilized to detect the protein-protein interaction. The phosphorylation of p53 was evaluated by in vitro kinase assay. Poly-ubiquitination of p53 was examined by in vivo ubiquitination assay. Cell growth and apoptosis, ROS levels and DNA damage response were measured for functional analyses.

Results: We showed that CDK16 is frequently overexpressed in lung cancer cells and tissues, and high levels of CDK16 are correlated with lymph node stage and poor prognosis in lung cancer patients. Furthermore, we provided evidence that CDK16 binds to and phosphorylates p53 at Ser315 site to inhibit transcriptional activity of p53. Moreover, we uncovered that this phosphorylation modification accelerates p53 degradation via the ubiquitin/proteasome pathway. Importantly, we demonstrated that CDK16 promotes radioresistance by suppressing apoptosis and ROS production as well as inhibiting DNA damage response in lung cancer cells in a p53-dependent manner.

Conclusion: Our findings suggest that CDK16 negatively modulates p53 signaling pathway to promote radioresistance, and therefore represents a promising therapeutic target for lung cancer radiotherapy.

Keywords: CDK16, p53, radioresistance, phosphorylation, lung cancer.

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How to cite this article:
Xie J, Li Y, Jiang K, Hu K, Zhang S, Dong X, Dai X, Liu L, Zhang T, Yang K, Huang K, Chen J, Shi S, Zhang Y, Wu G, Xu S. CDK16 Phosphorylates and Degrades p53 to Promote Radioresistance and Predicts Prognosis in Lung Cancer. Theranostics 2018; 8(3):650-662. doi:10.7150/thno.21963. Available from http://www.thno.org/v08p0650.htm