COTE1 Regulates AMPKα2 Deubiquitination by Targeting WWP1 Activation to Promote Proliferation and Autophagy in Small Cell Lung Cancer

Abstract

COTE1 expression is significantly upregulated in small cell lung cancer (SCLC) tissues compared to normal lung tissues and promotes SCLC cell proliferation and migration. However, the mechanism by which COTE1 promotes these behaviors in SCLC is unclear. This study aimed to explore the role and mechanism of COTE1 in promoting the progression of SCLC and to identify potential targets for the clinical treatment of SCLC. The cells were transfected with the COTE1 overexpression plasmid or WWP1 overexpression plasmid (WT, MUT), etc., and the expression of AMPKα2 was detected via qRT-PCR and western blotting. Double immunofluorescence staining was used to observe the colocalization of COTE1 and WWP1, and protein interactions between COTE1 and WWP1 were analyzed via Co-IP. CCK-8, cell colony formation, scratch wound healing, and Transwell assays were used to assess cell proliferation, migration, and invasion. Transmission electron microscopy was used to observe cell autophagy, and western blotting was used to analyze the expression of the autophagy-related proteins AMPKα2 and p-ULK1 (Ser555). A mouse model was used to verify the effects of COTE1 on SCLC tumor growth and autophagy. We found via cell-based and In Vivo experiments that COTE1 binds to WWP1 and that high expression of COTE1 alters WWP1 expression, which in turn mediates AMPKα2 deubiquitination and promotes SCLC cell proliferation, migration, tumorigenicity, and autophagy. The overexpression of WWP1 (MUT) reversed the above effects of COTE1 on SCLC cells. In conclusion, COTE1 regulates AMPKα2 deubiquitination by targeting WWP1 activation to promote the proliferation and autophagy of SCLC cells.

Keywords: AMPKα2 ubiquitylation; COTE1; E3 ubiquitin protein ligase 1; autophagy; small cell lung cancer.