Abstract
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.
Highlights
Lung cancer is the leading cause of cancer-related incidents and mortality worldwide, with an estimated 1.8 million new lung cancer cases in 2012 [1]
To further determine the expression of TC2N in lung cancer patients, we examined the levels of TC2N protein on a tissue microarray (TMA) containing 272 lung tumor tissues and 265 paired adjacent non-tumor tissues
We identified TC2N as a novel oncogene acting through suppression of p53 signaling pathway in human lung cancer
Summary
Lung cancer is the leading cause of cancer-related incidents and mortality worldwide, with an estimated 1.8 million new lung cancer cases in 2012 [1]. Despite improvements in therapeutic strategies, lung cancer still has an extremely poor prognosis, with a 5-year survival rate of ~20% [2]. The late diagnosis and lack of effective therapy are the main reasons leading to the poor prognosis of patients with lung. Tac2-N (TC2N), located on human chromosome 14q32.12, encodes a putative C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family. TC2N was first cloned in the mouse, and this protein contains two C-terminal C2 domains, C2A and C2B [6]. Further studies indicated that the function of the C2 domain is not limited to calcium-dependent phospholipid binding, since this motif has been implicated in cellular signal transduction and protein–protein interactions [10]. Few studies have investigated the role and mechanism of TC2N in cancer
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