TC2N, a novel oncogene, accelerates tumor progression by suppressing p53 signaling pathway in lung cancer

被引:41
作者
Hao, Xiang-lin [1 ]
Han, Fei [1 ]
Zhang, Ning [1 ]
Chen, Hong-qiang [1 ]
Jiang, Xiao [1 ]
Yin, Li [1 ]
Liu, Wen-bin [1 ]
Wang, Dan-dan [1 ]
Chen, Jian-ping [1 ]
Cui, Zhi-hong [1 ]
Ao, Lin [1 ]
Cao, Jia [1 ]
Liu, Jin-yi [1 ]
机构
[1] Third Mil Med Univ, Coll Prevent Med, Inst Toxicol, Chongqing 400038, Peoples R China
基金
中国国家自然科学基金;
关键词
CELL NEUROENDOCRINE CARCINOMA; DNA-BINDING; PHOSPHORYLATES P53; C2; DOMAINS; MYOFERLIN; GENE; PROTEIN; GROWTH; TRANSCRIPTION; PROMOTES;
D O I
10.1038/s41418-018-0202-8
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 CdkS degradation or disrupting the interaction between CdkS 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.
引用
收藏
页码:1235 / 1250
页数:16
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