Dietary Serine Restriction Impacts H3K27 and H3K4 Methyl Epigenomes to Impede Head and Neck Cancer Cell Plasticity and Tumor Growth

Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy characterized by high morbidity, therapeutic resistance and intratumoral heterogeneity driven by plastic cell states. Given that metabolic inputs can shape cell identities via epigenetic mechanisms, we investigated how metabolism of a non-essential amino acid, serine, affects histone modifications with key roles in cell plasticity: H3K27me3, which represses differentiation genes, and H3K4me3 which activates stemness and epithelial-to-mesenchymal transition (EMT) genes. Using a panel of human OSCC patient-derived cell lines and an orthotopic murine isograft model, we show that OSCC cells depend on exogenous serine for proliferation. Dietary serine deprivation induced de novo serine synthesis with a concomitant increase in a-ketoglutarate (aKG), a cofactor for KDM6B and KDM5A/B demethylases of H3K27me3 and H3K4me3, respectively. RNA-seq-derived serine deprivation gene signatures revealed activation of keratinization program and suppression of EMT and proliferation genes and tracked with good OSCC patient outcomes in TCGA. Furthermore, CUT & RUN profiling showed site-specific losses of H3K27me3 at differentiation genes and reduction of H3K4me3 at stemness, EMT and cell cycle genes. However, inhibition of aKG with 2-hydroxyglutarate was not sufficient to rescue cell proliferation. Instead, genome-wide analysis revealed widespread H3K27me3-H3K4me3 bivalency, with extensive transcriptional repression of proliferation and oncogenic programs. Functionally, serine deprivation impaired orthotopic tumor growth and improved the immune landscape in syngeneic mice. Our studies identify a metabolic serine-aKG-KDM-H3K27me3/H3K4me3 bivalency axis that globally reprograms OSCC chromatin as a potential therapeutic strategy to impede tumor plasticity and evolution to advanced disease.