Abstract
BackgroundA number of studies have indicated that Ubiquitin-conjugating enzyme E2T (UBE2T), as an oncogene, promotes progression and metastasis of lung cancer, including lung adenocarcinoma (LUAD), but it is completely unknown whether and how UBE2T is ubiquitylated and degraded, and by which E3 ligase. NEDD4L plays a critical role in the regulation of cellular processes of various cancers, most of which is attributed to its E3 ubiquitin ligase function. However, the relationship between NEDD4L and UBE2T in LUAD has not been elucidated.MethodsThe relationship between NEDD4L and UBE2T in LUAD tissues and cells was found by bioinformatic analyses and immunoblotting. Cell counting kit-8, colony formation assay, half-life analysis and the in vivo ubiquitylation assay, generation of xenograft model were performed to determine how NEDD4L regulates UBE2T and its downstream signaling pathway in vitro and in vivo.ResultsBioinformatic analyses found that NEDD4L, as a potential correlation E3 ligase of UBE2T, was negatively correlated with UBE2T in LUAD. Consistently, UBE2T protein half-life was shortened or extended by NEDD4L overexpression or depletion, respectively. NEDD4L inhibited LUAD cell progression in vitro and in vivo via inducing the ubiquitination-mediated UBE2T degradation, which repressed PI3K-AKT signaling. Similarly, NEDD4L predicted a better patient survival, whereas UBE2T predicted a worse survival.ConclusionsCollectively, our results reveal that NEDD4L is a novel E3 ligase of UBE2T, which can inhibit PI3K-AKT signaling by targeting for UBE2T ubiquitination and degradation, resulting in repression of LUAD cell progression.
Highlights
Lung cancer is still the leading cause of cancer-related death around the world [1], and late diagnosis is a fundamental obstacle to improving lung cancer methods [2]
Integrated analysis of lung cancer reveals that NEDD4L may be an E3 ligase for Ubiquitin-conjugating enzyme E2T (UBE2T) UBE2T was highly expressed in lung cancer, and its protein expression was negatively correlated with the survival of lung cancer patients [13, 17]
Kaplan–Meier survival analysis indicated that patients with higher expression of NEDD4L were related to a better overall survival (Fig. 1g), whereas patients with higher expression of UBE2T were related to a worse overall survival (Fig. 1E)
Summary
Lung cancer is still the leading cause of cancer-related death around the world [1], and late diagnosis is a fundamental obstacle to improving lung cancer methods [2]. Several lines of investigation revealed that UBE2T promoted proliferation and EMT by ubiquitination-mediated FOXO1 degradation and Wnt/ β-catenin signaling pathway activation in NSCLC cells [13, 18]. It is unknown how UBE2T is regulated at the post-translational level and by which E3 ligase. A number of studies have indicated that Ubiquitin-conjugating enzyme E2T (UBE2T), as an oncogene, promotes progression and metastasis of lung cancer, including lung adenocarcinoma (LUAD), but it is completely unknown whether and how UBE2T is ubiquitylated and degraded, and by which E3 ligase. The relationship between NEDD4L and UBE2T in LUAD has not been elucidated
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