Glutamine is heavily consumed by tumours. Yet, the regional effects of glutamine deprivation within tumours are unknown. Pan et al. show that low glutamine in the tumour core results in increased histone hypermethylation through a decrease inα-ketoglutarate levels. Depleted glutamine-mediated histone hypermethylation causes cellular dedifferentiation of patient-derived BRAFV600E melanoma cells and resistance to BRAF inhibition via histone methylation on H3K27. This study highlights how regional differences in nutrient availability can influence tumour cell differentiation and drug sensitivity.