alpha-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer

Genetic-driven deregulation of the Wnt pathway is crucial but not sufficient for colorectal cancer (CRC) tumorigenesis. 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 (alpha KG) levels. alpha KG supplementation is sufficient to rescue low-glutamine-induced stemness and Wnt hyperactivation. Mechanistically, we found that alpha KG promotes hypomethylation of DNA and histone H3K4me3, leading to an upregulation of differentiation-associated genes and downregulation of Wnt target genes, respectively. Using organoids derived from patients with CRC and several in vivo CRC tumor models, we show that alpha KG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumor growth and extending survival. Together, our results reveal how the metabolic microenvironment impacts Wnt signaling and identify alpha KG as a potent antineoplastic metabolite for potential differentiation therapy for patients with CRC.