Oncogenic and immunomodulatory functions of SUV420H1 in HPV-negative head and neck squamous cell carcinoma

  • bioRxiv. 2025 Oct 20:2025.10.20.683419. doi: 10.1101/2025.10.20.683419.
Arfa Moshiri  1 ,  Marie Luff  1 ,  Sohyoung Kim  2 ,  Meiye Jiang  1 ,  Mohd Saleem Dar  1 ,  Malhar Patel  1 ,  Katherine McKinnon  3 ,  Elijah F Edmondson  4 ,  Jawad Akhtar  1 ,  Hui Cheng  5 ,  Vassiliki Saloura  1
Affiliations
  • 1. Thoracic and GI Malignancies Branch, National Institutes of Health, Bethesda, MD.
  • 2. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD.
  • 3. Center for Cancer Research, Office of Science and Technology Resources, Flow Cytometry Core, National Cancer Institute, Bethesda, MD 20892 USA.
  • 4. Molecular Histopathology Laboratory, National Institutes of Health, Frederick, MD.
  • 5. National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD.
PMID: 41473330 DOI: 10.1101/2025.10.20.683419
Abstract

Despite the advent of immunotherapy, human-papilloma-virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) carries a high morbidity and mortality rate, thus novel therapies are urgently needed. Suppressor Of Variegation 4-20 Homolog 1 (SUV420H1) is a protein lysine methyltransferase that writes H4K20me3. Approximately 35% of HPV-negative HNSCC tumors carry gains/amplifications of SUV420H1. Gene Set Enrichment Analysis (GSEA) showed enrichment of proliferation-, epithelial-mesenchymal transition (EMT)- and immune-response pathways in SUV420H1-overexpressing HPV-negative HNSCC tumors. Depletion of SUV420H1 led to decreased proliferation, cell cycling and invasion in human HPV-negative HNSCC cell lines, while enzymatic inhibition decreased the invasive capacity but not the proliferation and cell cycling of HPV-negative HNSCC cell lines, supporting the presence of catalytically-independent and -dependent functions of SUV420H1. In a syngeneic mouse model of mouse oral carcinoma 1 tumors (MOC1), Suv420h1 knockout (KO) in MOC1 Cancer cells halted tumor growth and synergized with anti-PD-1 therapy. In the tumor immune microenvironment (TIME) of Suv420h1 KO MOC1 tumors, a significant increase in the macrophage compartment with a concurrent decrease in the protumorigenic granulocytic myeloid derived suppressor cells (gMDSCs) was observed. Genome-wide mapping of SUV420H1-mediated H4K20me3 revealed enrichment of EMT-, IFN-response, and myeloid-attracting chemokines. This work provides rationale for the depletion/degradation of SUV420H1 as a novel therapeutic strategy to hinder proliferation and invasion, and to impart sensitization to anti-PD-1 immunotherapy for patients with HPV-negative HNSCC tumors with SUV420H1 gain/amplification.

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