Collagen prolyl 4-hydroxylase subunit α member-induced head and neck squamous cell carcinoma aggressiveness is antagonized by LLGL2 via reduced expression of occludin

• Higher expression of all three C-P4HA isoforms is a superior prognostic indicator in HNSC compared to expression of one or two isoforms. • LLGL2 is identified as a novel antagonist of C-P4HA-induced cancer aggressiveness, with its silencing upregulating occludin and enhancing invasion/migration. • Simultaneous knockdown of all three C-P4HAs more effectively inhibits HNSC cell migration and invasion than individual knockdowns. • High LLGL2 expression correlates with improved prognosis in HNSC patients, suggesting a potential therapeutic target for mitigating tumor progression.