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Association of Uba6-Specific-E2 (USE1) With Lung Tumorigenesis
Seong-Jin Kim1, Tae Hyeong Lee1, Sang Hee Nam1
1Department of Biomedical Sciences, University of Ulsan College of Medicine, ASAN Medical Center, Seoul, Korea.
Background:
The UBA6-specific E2 conjugating enzyme 1 (USE1) ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We investigated whether the UBA6-USE1 enzyme cascade plays a role in lung cancer tumorigenesis.
Methods:
USE1 expression was assessed in tumor-normal paired samples from 106 lung cancer patients by immunoblot. USE1 was stably overexpressed and knocked down in lung cancer cell lines to evaluate cell proliferation, colony formation, and invasion. Xenograft models were used to determine the effects of USE1 on tumor growth (n = 7). Proteomics analysis was used to identify proteins interacting with USE1. The USE1 gene was sequenced in lung cancer patients, and missense mutations of USE1 were generated to evaluate its function. All statistical tests were two-sided.
Results:
USE1 proteins were frequently overexpressed in lung cancer patients (92.5%) Stable overexpression of USE1 increased cell proliferation ( P = .002), migration ( P < .001), and invasion ( P < .001), whereas knockdown of USE1 reduced cell proliferation ( P < .001), migration ( P = .003), and invasion in lung cancer cells and xenograft models ( P < .001). USE1 was found to have a conserved D-box domain, and the level of the protein was regulated by the anaphase-promoting complex. Several missense mutations in USE1 identified in patients prolong the stability of the protein.
Conclusions:
USE1 proteins are frequently overexpressed in lung cancer, and missense mutations in USE1 prolong the half-life of the protein, promoting tumor formation. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment.