The protein containing the C2 domain has been well documented for its essential roles in endocytosis, cellular metabolism and cancer. Tac2-N (TC2N) is a tandem C2 domain-containing protein, but its function, including its role in tumorigenesis, remains unknown. Here, we first identified TC2N as a novel oncogene in lung cancer. TC2N was preferentially upregulated in lung cancer tissues compared with adjacent normal lung tissues. High TC2N expression was significantly associated with poor outcome of lung cancer patients. Knockdown of TC2N markedly induces cell apoptosis and cell cycle arrest with repressing proliferation in vitro, and suppresses tumorigenicity in vivo, whereas overexpression of TC2N has the opposite effects both in vitro and in vivo. Using a combination of TCGA database and bioinformatics, we demonstrate that TC2N is involved in regulation of the p53 signaling pathway. Mechanistically, TC2N attenuates p53 signaling pathway through inhibiting Cdk5-induced phosphorylation of p53 via inducing Cdk5 degradation or disrupting the interaction between Cdk5 and p53. Moreover, the blockade of p53 attenuates the function of TC2N knockdown in the regulation of cell proliferation and apoptosis. In addition, downregulated TC2N is involved in the apoptosis of lung cancer cells induced by doxorubicin, leading to p53 pathway activation. Overall, these findings uncover a role for the p53 inactivator TC2N in regulating the proliferation and apoptosis of lung cancer cells. Our present study provides novel insights into the mechanism of tumorigenesis in lung cancer.
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This work was supported by the National Natural Science Foundation of China (Nos. 81773461 and 81573179). We would like to thank all patients involved in this study. The authors would like to thank American Journal Experts for language editing.
X-LH, FH, JC, LA, W-BL and J-YL were responsible for the experimental design. X-LH, NZ, D-DW and J-PC contributed to the execution of experiments, data statistics and manuscript composition. FH, NZ, H-QC and J-YL participated in performing the experiment and in the manuscript mapping and submission. X-LH, FH, W-BL, LY, XJ, Z-HC and J-YL participated in the discussion and interpretation of data. FH, LY, XJ, JC and J-YL conceived the study and revised the manuscript. FH, W-BL, JC and J-YL were responsible for the funding application, and the supervision and management of the project. All authors have contributed to and approved the final manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Edited by H.-U. Simon
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Cell Death & Disease (2019)