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

Mari B. Ishak Gabra, Ying Yang, Haiqing Li, Parijat Senapati, Eric A. Hanse, Xazmin H. Lowman, Thai Q. Tran, Lishi Zhang, Linda T. Doan, Xiangdong Xu, Dustin E. Schones, David A. Fruman and Mei Kong ()
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Mari B. Ishak Gabra: University of California, Irvine
Ying Yang: University of California, Irvine
Haiqing Li: City of Hope National Medical Center
Parijat Senapati: Beckman Research Institute of City of Hope Cancer Center
Eric A. Hanse: University of California, Irvine
Xazmin H. Lowman: University of California, Irvine
Thai Q. Tran: University of California, Irvine
Lishi Zhang: University of California
Linda T. Doan: UCI Health Dermatology Center
Xiangdong Xu: University of California San Diego
Dustin E. Schones: Beckman Research Institute of City of Hope Cancer Center
David A. Fruman: University of California, Irvine
Mei Kong: University of California, Irvine

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide 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.

Date: 2020
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DOI: 10.1038/s41467-020-17181-w

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