Stabilization of PTGES by deubiquitinase USP9X promotes metastatic features of lung cancer via PGE₂ signaling.

Early metastasis and local recurrence are the major causes of mortality and poor prognosis of non-small cell lung cancer (NSCLC). However, the underlying mechanisms of these processes are poorly understood. In this study, we aimed to investigate the roles of the PTGES/PGE₂ pathway in lung cancer progression. We found that prostaglandin E synthase (PTGES), a key enzyme for PGE₂ synthesis in the arachidonic acid pathway, was highly dysregulated in NSCLC. Dysregulated PTGES was essential for the promotion of tumor migration and metastasis of NSCLC cells. Knockdown of PTGES in lung cancer cells resulted in suppressed cell migration, which was reversed by exogenous PGE₂. Consistent with this, PTGES knockdown also reduced the expression of CSC markers, tumor sphere formation, colony forming activity, tumorigenicity, and lung metastasis in vivo. Dysregulated PTGES is mainly attributed to protein stabilization by USP9X, a deubiquitination enzyme. USP9X physically interacted with PTGES and prevented it from proteasome-directed degradation via deubiquitination. Consistent with this, USP9X expression was highly correlated with PTGES expression in NSCLC tumor tissues. Taken together, our results show that the upregulated USP9X-PTGES-PGE₂ axis contributes significantly to the metastatic features of NSCLC.

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