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<p>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, IP<sub>6</sub> kinase-2 (IP6K2), a 5-diphosphoinositol pentakisphosphate (5-IP<sub>7</sub>) synthase upregulated in patients with CRC, is activated via a ROS–Src phosphorylation axis elicited by dextran sulfate sodium (DSS), generating 5-IP<sub>7</sub> around adherens junction (AJ) to promote E-cadherin endocytosis and the transcriptional activities of β-catenin. Mechanistically, 5-IP<sub>7</sub> inhibits inositol 5-phosphatases such as OCRL to promote PI(4,5)P<sub>2</sub>-mediated endocytic adaptor recruitment. Depleting 5-IP<sub>7</sub> or overexpressing a 5-IP<sub>7</sub> 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<sup>−/−</sup> mice against DSS insult. Thus, 5-IP<sub>7</sub> is an oncometabolite whose stimulus-dependent synthesis relieves a PI(4,5)P<sub>2</sub> dephosphorylation-based endocytic checkpoint, leading to AJ disassembly and protumorigenic β-catenin activation. Targeting IP6K2 could strengthen intestinal epithelial barrier against inflammation and cancer.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年8月26日

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  • Hongyun Zhang,
  • Bobo Zhang,
  • Yuebo Zhao,
  • Yang Su,
  • Yifan Peng,
  • Xiaoli Yang,
  • Hongming Zhao,
  • Hongyu Liu,
  • Jie Feng,
  • Hongjing Pei,
  • Wenyong Zhang,
  • Niu Huang,
  • Kai Jiang,
  • Masatoshi Ito,
  • Guizhen Liu,
  • Nicolas Jork,
  • Karen E. Anderson,
  • Li Zhao,
  • Eiichiro Nagata,
  • Henning J. Jessen,
  • Philip T. Hawkins,
  • Changzheng Du,
  • Feng Rao

摘要

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.