Epigenetic silencing of GPD1 by HDAC2 via H3K9 deacetylation promotes head and neck squamous cell carcinoma progression

  • Exp Cell Res. 2026 Jun 15;459(2):115018. doi: 10.1016/j.yexcr.2026.115018.
Liqiong Xue  1 ,  Wenbo Tang  1 ,  Mingwang Zhou  2 ,  Qin Ling  3 ,  Jiuli Zhou  4
Affiliations
  • 1. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2. Tongji University School of Medicine, Shanghai, China.
  • 3. School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
  • 4. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 41962619 DOI: 10.1016/j.yexcr.2026.115018
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, migration 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 GPD1low/HDAC2high 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.

Keywords
Epigenetic modification; Glycerol-3-phosphate dehydrogenase 1; Head and neck cancer; Histone deacetylases 2; Histone deacetylation.
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