NEDD4L-induced ubiquitination mediating UBE2T degradation inhibits progression of lung adenocarcinoma via PI3K-AKT signaling

Abstract

Background 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. 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. Methods The 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. Results Bioinformatic 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. Conclusions Collectively, 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.

Peer Review #1 of "Down-regulated NEDD4L facilitates tumor progression through activating Notch signaling in lung adenocarcinoma (v0.1)"

“…In a previous study, the regulatory role of NEDD4L in Notch signalling has been revealed (21). (41). These results suggest that drugs which increase but not decrease NEDD4L expression might be beneficial for LUAD treatment.…”

UBE2T Promotes Temozolomide Resistance of Glioblastoma Through Regulating the Wnt/β-Catenin Signaling Pathway

“… 8 Further, UBE2T overexpression enhances malignant progression by activating the PI3K-AKT signaling pathway in ovarian cancer, lung adenocarcinoma, breast cancer, renal cell carcinoma, and osteosarcoma. 10 , 28–31 UBE2T significantly promotes retinoblastoma tumorigenesis via STAT3 signaling. 32 Notably, UBE2T induces Wnt/β-catenin pathway activation through RACK1 ubiquitination and degradation, resulting in promotion of gastric cancer progression.…”

Molecular Mechanism of Long Noncoding RNA SNHG14 in Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells through the NEDD4L/FOXA2/PCP4 Axis

“…NEDD4L as an E3 ubiquitin-protein ligase mediates ubiquitination modification to regulate the protein level [ 53 , 54 ], and our bioinformatics data suggested FOXA2 was a target of NEDD4L. FOX family members are essential for bone metabolism and function as regulators of OD of MSCs [ 28 , 55 – 57 ].…”