Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth
Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth
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DOI：
10.1038/s41467-020-17181-w
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发表时间：
2020-07-03
影响因子：
16.6
通讯作者：
Kong, Mei
中科院分区：
文献类型：
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作者：
Gabra, Mari B. Ishak;Yang, Ying;Kong, Mei
肿瘤细胞在体内适应营养缺乏，但针对营养贫乏微环境的策略仍未被探索。在黑色素瘤中，肿瘤细胞经常经历低水平的谷氨酰胺，这会促进细胞去分化。在这里，我们表明，饮食中补充谷氨酰胺显著抑制黑色素瘤生长，延长转基因黑色素瘤小鼠模型的生存时间，并增加对BRAF抑制剂的敏感性。代谢组学分析表明，饮食摄入谷氨酰胺有效地增加了肿瘤及其下游代谢物α-KG中的谷氨酰胺浓度，而不会增加细胞增殖所需的生物合成中间体。从机理上讲，我们发现补充谷氨酰胺会均匀地改变肿瘤中的转录组。我们的数据进一步表明，肿瘤内α-KG浓度的增加推动了H3K4me3的低甲基化，从而抑制了黑色素瘤中表观遗传激活的致癌途径。因此，我们的发现提供了证据，证明补充谷氨酰胺可以作为一种潜在的饮食干预，通过表观遗传重新编程来阻止黑色素瘤的生长，并使肿瘤对靶向治疗敏感。肿瘤微环境中养分的可获得性会影响肿瘤的生长。在这里，作者发现，在黑色素瘤小鼠模型中，喂食高谷氨酰胺饮食的小鼠肿瘤生长减少，对BRAF抑制剂的敏感性增加，α-酮戊二酸水平升高。
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, alpha KG, 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 alpha KG 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. The availability of nutrients within the tumour microenvironment can influence tumour growth. Here, the authors find that, in a melanoma mouse model, mice fed a high glutamine diet have reduced tumour growth, increased sensitivity to Braf inhibitors and elevated a-ketoglutarate levels.