Abstract
The deubiquitinase DUB3 is frequently overexpressed in non-small cell lung cancer (NSCLC) and contributes to its malignant phenotype. However, the underlying molecular mechanism of DUB3 in NSCLC is largely unknown. In this study, we report that DUB3 regulates cell cycle progression by deubiquitinating cyclin A that links to proliferation of NSCLC cells. We found that knockdown of DUB3 decreases cyclin A levels, whereas overexpression of DUB3 strongly increases cyclin A levels. Mechanistically, DUB3 interacts with cyclin A, which removes the polyubiquitin chains conjugated onto cyclin A and stabilizes the cyclin A protein. Furthermore, we demonstrate that DUB3 regulates cell cycle progression by stabilizing cyclin A, because ablation of DUB3 arrests cell cycle from G0/G1 to S phase and the resulting effect can be rescued by introducing cyclin A into NSCLC cells. Functionally, we found that the effect of DUB3 on cyclin A mediates proliferation of NSCLC cells. Moreover, a significant correlation between DUB3 abundance and cyclin A expression levels were also found in NSCLC samples. Taken together, these results reveal that DUB3 functions as a novel cyclin A regulator through maintaining cyclin A stability, and that the DUB3-cyclin A signaling axis plays a critical role in cell cycle progression for proliferation of NSCLC.
Highlights
Lung cancer is a frequently diagnosed malignancy with the highest morbidity and mortality around the world
We examined whether endogenous DUB3 by anti-Flag antibodies in DUB3-overexpressing cells but not in negative control cells transfected with interacts with cyclin A in A549 cells
We found that cyclin A was co-immunoprecipitated by anti-Flag antibodies in DUB3-overexpressing cells but not in negative control cells transfected with the same amount of empty vector (Figure 3A)
Summary
Lung cancer is a frequently diagnosed malignancy with the highest morbidity and mortality around the world. According to the latest Global Cancer Statistics 2018, lung cancer accounts for 11.6%. Of the total diagnosed cancer cases, and for 18.4% of the total cancer-related deaths [1]. Cell Lung Cancer (NSCLC) is the most common type of lung cancer, making up about 80–85% of all cases. Despite tremendous efforts in developing new therapeutic strategies for NSCLC, the overall. 5-year survival rates less than 15% [2]. It is urgent to elucidate the molecular mechanism of tumorigenesis for effective manipulation of NSCLC.
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