Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.

E-cadherin downregulation is an epithelial-mesenchymal transition hallmark canonically attributed to transcriptional repression. Here we delineate a metabolite-driven endocytic route of E-cadherin downregulation in inflammation-associated colorectal cancer (CRC). Specifically, IP6 kinase-2 (IP6K2), a 5-diphosphoinositol pentakisphosphate (5-IP7) synthase upregulated in patients with CRC, is activated via a ROS-Src phosphorylation axis elicited by dextran sulfate sodium (DSS), generating 5-IP7 around adherens junction (AJ) to promote E-cadherin endocytosis and the transcriptional activities of β-catenin. Mechanistically, 5-IP7 inhibits inositol 5-phosphatases such as OCRL to promote PI(4,5)P2-mediated endocytic adaptor recruitment. Depleting 5-IP7 or overexpressing a 5-IP7 binding-deficient OCRL mutant confers resistance to DSS-elicited AJ disruption. Intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC, whereas an IP6K2 isoform-selective inhibitor protects wild-type but not IP6K2-/- mice against DSS insult. Thus, 5-IP7 is an oncometabolite whose stimulus-dependent synthesis relieves a PI(4,5)P2 dephosphorylation-based endocytic checkpoint, leading to AJ disassembly and protumorigenic β-catenin activation. Targeting IP6K2 could strengthen intestinal epithelial barrier against inflammation and cancer.