E3 ubiquitin ligase MAGI3‑mediated TAZ ubiquitination suppresses the non‑small cell lung cancer occurrence and development by targeting the Wnt pathway.

Abstract

Membrane associated guanylate kinase WW and PDZ domain containing 3 (MAGI3) functions as a tumor suppressor in lung cancer, but its role and mechanism in non‑small cell lung cancer (NSCLC) progression remain unclear. MAGI3 expression was detected in NSCLC tissues (immunohistochemistry) and cell lines (western blotting). Tet‑on inducible MAGI3 overexpression was used to assess effects on NSCLC cells via Cell Counting Kit‑8, Transwell, colony/sphere formation, β‑Galactosidase staining and flow cytometry. Ubiquitination/half‑life assays analyzed MAGI3‑TAZ (transcriptional co‑activator with PDZ‑binding motif) interaction. In situ and xenograft tumor models evaluated tumor growth and metastasis. The Cancer Genome Atlas data, clinical samples, and cell lines showed downregulated MAGI3 in NSCLC, correlating with poor prognosis. MAGI3 overexpression reduced cell viability, clonogenicity, sphere formation, migration and invasion; induced G1 phase arrest (reduced CyclinD1) and cellular senescence. MAGI3 specifically promoted TAZ ubiquitination via PDZ domain‑mediated interaction, which subsequently blocked β‑catenin nuclear translocation, dampened Wnt signaling components (DVL2/phosphorylated GSK3β), and reduced TCF/LEF transcriptional output. Reconstitution of TAZ reversed MAGI3‑mediated inhibition of Wnt pathway markers (cMYC, c‑JUN, WISP1 and PPARD). In vivo, MAGI3 overexpression suppressed tumor growth and lung metastasis, while MAGI3 silencing increased metastatic nodules. The present study identified that MAGI3, as a suppressor in NSCLC progression, repressed the Wnt pathway‑including TAZ degradation, impaired β‑catenin nuclear translocation, and diminished TCF/LEF transcription‑thereby restraining tumorigenesis and metastasis of NSCLC.