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

Hongyun Zhang1, Bobo Zhang1, Yuebo Zhao1

  • 1School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.

Nature Chemical Biology
|August 26, 2025
PubMed

Insights

A metabolite called 5-diphosphoinositol pentakisphosphate (5-IP7) drives E-cadherin loss in colorectal cancer by promoting endocytosis. Targeting IP6K2, which produces 5-IP7, may protect the intestinal barrier against inflammation and cancer.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Metabolomics

Background:

  • E-cadherin downregulation is a hallmark of epithelial-mesenchymal transition, typically linked to transcriptional repression.
  • Inflammation-associated colorectal cancer (CRC) presents unique mechanisms for E-cadherin loss.
  • Adherens junction (AJ) integrity is crucial for epithelial barrier function.

Purpose of the Study:

  • To investigate a metabolite-driven pathway for E-cadherin downregulation in inflammation-associated colorectal cancer.
  • To elucidate the role of IP6 kinase-2 (IP6K2) and its product 5-diphosphoinositol pentakisphosphate (5-IP7) in E-cadherin endocytosis.
  • To explore the therapeutic potential of targeting IP6K2 in CRC and colitis.

Main Methods:

  • Utilized dextran sulfate sodium (DSS) model to induce inflammation and colitis/CRC in mice.
  • Investigated the activation of IP6K2 via a ROS-Src phosphorylation axis.
  • Examined the effect of 5-IP7 on inositol 5-phosphatases (e.g., OCRL) and PI(4,5)P2 levels.
  • Assessed the impact of IP6K2 deletion and pharmacological inhibition on AJ integrity and disease progression.

Main Results:

  • IP6K2, upregulated in CRC patients, generates 5-IP7, promoting E-cadherin endocytosis and β-catenin activation via ROS-Src signaling.
  • 5-IP7 inhibits OCRL, leading to PI(4,5)P2 accumulation and endocytic adaptor recruitment.
  • Depletion of 5-IP7 or a non-binding OCRL mutant conferred resistance to DSS-induced AJ disruption.
  • Intestinal IP6K2 deletion attenuated DSS-induced colitis/CRC; an IP6K2 inhibitor protected wild-type mice.

Conclusions:

  • 5-IP7 acts as an oncometabolite, relieving an endocytic checkpoint to drive AJ disassembly and promote CRC.
  • Targeting IP6K2 offers a potential strategy to reinforce the intestinal epithelial barrier against inflammation and cancer.
  • This study reveals a novel metabolite-driven mechanism for E-cadherin loss in colorectal cancer.

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