谷氨酰胺
生物
癌症研究
EZH2型
脱甲基酶
组蛋白
表观遗传学
黑色素瘤
甲基转移酶
DNA甲基化
组蛋白甲基化
甲基化
生物化学
氨基酸
DNA
基因表达
基因
作者
Min Pan,Michael A. Reid,Xazmin H. Lowman,Rajan P. Kulkarni,Trac D. Tran,Xiaojing Liu,Ying Yang,Jenny E. Hernandez-Davies,Kimberly K. Rosales,Haiqing Li,Willy Hugo,Chunying Song,Xiangdong Xu,Dustin E. Schones,David K. Ann,Viviana Gradinaru,Roger S. Lo,Jason W. Locasale,Mei Kong
摘要
Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids. Low glutamine in tumour core regions led to dramatic histone hypermethylation due to decreased α-ketoglutarate levels, a key cofactor for the Jumonji-domain-containing histone demethylases. Using patient-derived (V600E)BRAF melanoma cells, we found that low-glutamine-induced histone hypermethylation resulted in cancer cell dedifferentiation and resistance to BRAF inhibitor treatment, which was largely mediated by methylation on H3K27, as knockdown of the H3K27-specific demethylase KDM6B and the methyltransferase EZH2 respectively reproduced and attenuated the low-glutamine effects in vitro and in vivo. Thus, intratumoral regional variation in the nutritional microenvironment contributes to tumour heterogeneity and therapeutic response.
科研通智能强力驱动
Strongly Powered by AbleSci AI