Abstract 2720: Investigating the functional role of SUV420H1 in HPV-negative head and neck squamous cell carcinoma

Abstract Human Papilloma Virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a significant clinical challenge due to limited treatment options and poor prognosis. SUV420H1, encoding a protein lysine methyltransferase (PMT) responsible for H4K20 trimethylation (H4K20me3), is recurrently amplified in approximately 5% of HPV-negative HNSCC tumors, indicating a potential oncogenic role. Our previous studies demonstrated that while SUV420H1 depletion using siRNAs reduced the proliferation and colony-forming capacity in HPV-negative HNSCC cell lines, enzymatic inhibition with the SUV420H1 inhibitor A-196 induced only a modest effect in these phenotypes. In this study, we generated enzymatically inactive SUV420H1 mutants with a confirmed decrease in global H4K20me3 levels and conducted proliferation and colony-forming assays which concordantly showed only a modest effect in these phenotypes. GSEA analysis of RNA-seq obtained from HPV-negative HNSCC cells treated with SUV420H1 siRNAs or the SUV420H1 inhibitor A-196 showed commonly enriched pathways, including EMT, cell cycle and proliferation, and interferon alpha response pathways. In vivo experiments using Suv420h1 knockout (KO) MOC1 mouse cell lines in a syngeneic HPV-negative HNSCC flank mouse model demonstrated a marked decrease in tumor size. Furthermore, tumor flow cytometry revealed increased CD8+ T-cell, B-cell and macrophage infiltration. These findings provide strong evidence for the role of SUV420H1 in modulating immune responses. Ongoing studies aim to evaluate the combinatorial impact of SUV420H1 depletion and anti-PD-1 therapy in vivo to determine whether SUV420H1 loss sensitizes tumors to immune checkpoint blockade. Collectively, our data supports SUV420H1 as a potential therapeutic target in HPV-negative HNSCC. Citation Format: Arfa Moshiri, Sohyoung Kim, Marie Luff, Vassiliki Saloura. Investigating the functional role of SUV420H1 in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2720.