Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. We recently found, in melanoma, tumour cells often experience low glutamine levels, which induce histone hypermethylation, promote dedifferentiation, and increase resistance to BRAF inhibitors. These findings raise the possibility that increased glutamine levels can be detrimental to melanoma tumours. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in transgenic mouse model, and increases sensitivity to BRAF targeted inhibitors in both melanoma xenograft and patient-derived xenograft (PDX) models. Notably, metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine and its downstream metabolite, aKG, in serum and tumours, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome and suppresses expression of many melanoma-associated genes. Our data further demonstrate that increase in intra-tumoural aKG concentration, following glutamine supplementation, drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide important evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming. Overall design: Comparison of mRNA and gene expression profiles in control versus glutamine high melanoma tumors.