P4HA2 mediates hypoxia-induced collagen remodeling to promote tumor progression in head and neck squamous cell carcinoma

This study investigated the clinical significance, regulatory mechanisms, and functional roles of Prolyl 4-Hydroxylase Subunit Alpha 2 (P4HA2) in head and neck squamous cell carcinoma (HNSCC), focusing on its involvement in hypoxia-driven extracellular matrix (ECM) remodeling and tumor progression. Immunohistochemical (IHC) analysis was performed on 108 clinical HNSCC specimens to evaluate the expression of P4HA2 and Hypoxia-Inducible Factor-1 Alpha (HIF-1α) and their association with patient prognosis. These clinical findings were further validated using bioinformatic data from public cohorts. The transcriptional regulation of P4HA2 by HIF-1α under hypoxic conditions was investigated via chromatin immunoprecipitation (ChIP). Functional assays, including assessments of P4HA2’s dependency on its essential cofactor vitamin C, were conducted in HNSCC cell lines to evaluate cell proliferation, migration, and invasion in vitro. The role of P4HA2 in tumor growth and microenvironmental remodeling in vivo was examined using xenograft mouse models. P4HA2 and HIF-1α were upregulated in HNSCC and associated with poor prognosis. Hypoxia-induced HIF-1α directly activated P4HA2 transcription. P4HA2 promoted collagen deposition and ECM remodeling, facilitating HNSCC cell proliferation, migration, and invasion, with its collagen-producing effects enhanced by vitamin C. In vivo, P4HA2 overexpression accelerated tumor growth, accompanied by enhanced HIF-1α signaling and collagen production. P4HA2 is a key effector of the hypoxia/HIF-1α axis, driving collagen remodeling to promote HNSCC progression, suggesting its potential as a therapeutic target.