FBXL18 promotes cell proliferation by inducing K63-linked ubiquitination of PTEN in NSCLC cells

Purpose: We aim to investigate the role of E3 ubiquitin ligase FBXL18 in promoting non-small cell lung cancer (NSCLC) progression through the K63-linked ubiquitination of PTEN, thereby activating the PI3K/AKT signaling pathway. Methods: Forty-seven pairs of fresh NSCLC samples and adjacent para-cancerous tissues were collected from the patients at the time of surgical resection. The human NSCLC cell lines A549, H1299, H460, SPCA-1 were purchased from the cell bank of the Committee on Type Culture Collection of the Chinese Academy of Sciences (CTCC, Shanghai, China). Results : The study's results demonstrate that FBXL18 is upregulated in NSCLC and correlates with poor patient prognosis. Mechanistically, FBXL18 interacts with PTEN, inhibits its activity by inducing its K63-linked ubiquitination and promotes AKT phosphorylation and activation. In human NSCLC specimens, the expression of FBXL18 was upregulated and correlated with poor prognosis. Taken together, we uncover a new potential therapeutic targeting molecular mechanism by which FBXL18 activates PTEN/PI3K/AKT signaling pathway in NSCLC. Conclusions : FBXL18, an E3 ubiquitin ligase, upregulates in NSCLC and promotes tumor growth by activating the PTEN/PI3K/AKT pathway through K63-linked ubiquitination of PTEN. Clinical relevance is further supported by the positive correlation between FBXL18 expression and activation of the PI3K-AKT pathway in NSCLC patients.