Wnt信号通路
H3K4me3
下调和上调
生物
结直肠癌
癌症研究
细胞生物学
表观遗传学
癌症
信号转导
基因
遗传学
基因表达
发起人
作者
Trac D. Tran,Eric A. Hanse,Amber N. Habowski,Haiqing Li,Mari B. Ishak Gabra,Ying Yang,Xazmin H. Lowman,Amelia M. Ooi,Shu-Yuan Liao,Robert A. Edwards,Marian L. Waterman,Mei Kong
出处
期刊:Nature cancer
[Springer Nature]
日期:2020-03-20
卷期号:1 (3): 345-358
被引量:83
标识
DOI:10.1038/s43018-020-0035-5
摘要
Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumourigenesis. Here, we show that environmental glutamine restriction further augments Wnt signaling in APC mutant intestinal organoids to promote stemness and leads to adenocarcinoma formation in vivo via decreasing intracellular alpha-ketoglutarate (aKG) levels. aKG supplementation is sufficient to rescue low-glutamine induced stemness and Wnt hyperactivation. Mechanistically, we found that aKG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. Together, our results reveal how metabolic microenvironment impacts Wnt signaling and identify aKG as a potent antineoplastic metabolite for potential differentiation therapy for CRC patients.
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