{"doi":"10.1101/2025.10.20.683419","title":"Oncogenic and immunomodulatory functions of SUV420H1 in HPV-negative head and neck squamous cell carcinoma","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":578660,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.961,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":347766,"name":"Marie K. Luff","orcid":"0000-0003-4137-3930","position":1,"is_corresponding":false},{"id":651189,"name":"Sohyoung Kim","orcid":"0000-0002-6140-7918","position":2,"is_corresponding":false},{"id":1427387,"name":"Meiye Jiang","orcid":"0000-0002-3253-5531","position":3,"is_corresponding":false},{"id":338750,"name":"Mohd Saleem Dar","orcid":"0000-0003-4925-6819","position":4,"is_corresponding":false},{"id":1488573,"name":"Malhar Patel","orcid":"0000-0003-3052-0931","position":5,"is_corresponding":false},{"id":893924,"name":"Katherine McKinnon","orcid":"0000-0002-8281-3077","position":6,"is_corresponding":false},{"id":279369,"name":"Elijah F. Edmondson","orcid":"0000-0002-6106-3705","position":7,"is_corresponding":false},{"id":1249570,"name":"Jawad Akhtar","orcid":null,"position":8,"is_corresponding":false},{"id":1488574,"name":"Hui Cheng","orcid":"0000-0001-9154-9282","position":9,"is_corresponding":false},{"id":693771,"name":"Vassiliki Saloura","orcid":"0000-0002-9736-8578","position":10,"is_corresponding":false},{"id":1047444,"name":"Arfa Moshiri","orcid":"0000-0001-8030-0190","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:58:24.957414Z","pmid":"41473330","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}