Dietary serine restriction reduces head and neck cancer cell plasticity through epigenetic changes in the chromatin landscape [RNA-seq]

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 fate decisions. We now report that human OSCC cells behave like serine auxotrophs, depending on exogenous serine to promote growth and sustain plastic cell states, such as cancer stem cells and cells with EMT features.

We show that restriction of serine induces endogenous serine synthesis and generates alpha-ketoglutarate (aKG), a co-substrate for JMJD3 nuclear dioxygenase, which demethylates H3K27me3 and de-represses differentiation genes. This is balanced by the loss of H3K4me3 and inhibition of stemness genes. Likewise, dietary serine restriction inhibits orthotopic OSCC growth in syngeneic mice.