Abstract

Background Head and neck squamous cell carcinoma (HNSCC) remains a lethal malignancy with its pathogenic mechanisms incompletely unraveled. This study interrogates the role of the HDAC2-GPD1 axis in driving HNSCC progression. Methods HDAC2 and GPD1 expression was analyzed in HNSCC tissues (IHC) and cell lines (RT-qPCR). TCGA-HNSCC dataset (520 tumors, 44 normal controls) was used for bioinformatics analysis of gene expression, correlation, and prognostic value. Stable HNSCC cell lines with HDAC2/GPD1 overexpression or knockout were established via lentiviral infection. CCK-8, Transwell, wound healing, and flow cytometry were performed to assess cell proliferation, invasion, and apoptosis in vitro . ChIP assays were conducted to verify the binding of HDAC2 to the GPD1 promoter and the H3K9ac modification of GPD1. Nude mice were implanted with modified FaDu cells to assess tumor growth via tumor measurements and HE analyses. Results HDAC2 was upregulated while GPD1 was downregulated in HNSCC tissues and cell lines, consistent with TCGA data. TCGA analysis showed an inverse correlation between HDAC2 and GPD1 ( R = -0.2, P = 2.8e-06) and a poor prognostic trend in the GPD1 low /HDAC2 high subgroup. Lentivirus-mediated HDAC2 overexpression or GPD1 knockdown in HNSCC cells enhanced proliferation, invasion, and migration, while suppressing apoptosis. Conversely, GPD1 overexpression reversed these malignant phenotypes. ChIP assays confirmed HDAC2 binding to the GPD1 promoter, reducing H3K9 acetylation to repress GPD1 transcription. In vivo , Santacruzamate A (SCA) (an HDAC2 inhibitor) significantly inhibited xenograft tumor growth and restored GPD1 expression. Modified FaDu cell-derived xenografts showed that GPD1 knockdown accelerated tumor growth, which was inhibited by SCA. Conclusions HDAC2 represses GPD1 via H3K9 deacetylation to promote HNSCC progression, highlighting the HDAC2-GPD1 axis as a potential therapeutic target.