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

Head and neck cancer with its major subsite, oral squamous cell carcinoma (OSCC), is a devastating malignancy with limited treatment options. Given that recent advances in nutritional interventions have been recognized as potential strategies for targeting cancer, we investigated the role of dietary serine restriction in OSCC cell plasticity. Utilizing multiple human OSCC-derived cell lines and an orthotopic syngeneic mouse model of OSCC, we interrogated the impact of serine deprivation on this malignancy through biochemical assays, transcriptomic analyses, and CUT&RUN sequencing, as well as impact on tumor growth and its immune environment. We report that human OSCC cells behaved like serine auxotrophs, depending on exogenous serine for growth and maintenance of plastic cell states. We show that dietary restriction of serine induced endogenous serine synthesis and generated alpha-ketoglutarate (αKG), a co-substrate for JMJD3 nuclear dioxygenase, which demethylates H3K27me3 and de-represses differentiation genes. This was accompanied by the reduction of H3K4me3 at stemness and epithelial-to-mesenchymal transition (EMT) genes caused. Likewise, dietary serine restriction inhibited orthotopic OSCC isograft growth in mice concomitant with downregulation of H3K27me3 and increased immune infiltration in the tumor periphery. Collectively, our study provides new insights into the epigenetic etiology of OSCC that reveals the interplay between serine metabolism and epigenetic molecular mechanisms driving OSCC cell plasticity and tumorigenesis. The dependence of OSCC cells on exogenous serine to maintain plastic cell states offers a unique opportunity to utilize a non-toxic dietary serine restriction as an intervention treatment either alone or in combination with other therapies for OSCC patients.