Abstract
Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, presents significant public health challenges due to its genetic instability and late-stage diagnosis. Despite advancements in treatment, the median overall survival remains below one year, emphasizing the need for improved detection, prognosis, and therapeutic strategies. This study investigates the role of KDM4C and its interaction with GATA1 in regulating heme metabolism and tumor progression in HNSCC. KDM4C knockdown (KDM4C-KD) hindered HNSCC cell migration using in vitro assays, inhibited metastasis through zebrafish xenotransplantation, and suppressed tumor growth in mouse xenograft models. RNA-seq and CUT&Tag-seq analyses on KDM4C-KD SAS cells identified KDM4C-regulated genes, including ferrochelatase (FECH), in heme metabolism. Immunoprecipitation and docking analyses confirmed the KDM4C-GATA1 interaction. Notably, FECH overexpression in KDM4C or GATA1 knockdown cells restored cell migration, invasion, and proliferation, highlighting FECH as a crucial downstream target. KDM4 inhibitors myricetin and BPRKD022S0 (22S0) increased H3K9me3 levels, downregulated heme metabolism genes, and reduced cell survival in HNSCC cells. Zebrafish and mouse models demonstrated that these inhibitors effectively suppressed tumor growth and metastasis. Immunohistochemical analysis of HNSCC patient samples revealed high KDM4C and GATA1 expression correlated with advanced clinical stages and poor survival outcomes. Our findings elucidate the critical role of the KDM4C/GATA1-FECH axis in HNSCC progression and suggest that targeting this pathway with KDM4 inhibitors shows promising therapeutic potential for HNSCC treatment.