Abstract

Over-intake of dietary iron and hereditary iron overload are implicated in colorectal cancer (CRC) carcinogenesis, yet the mechanistic basis of how iron-mediated signaling leads to oncogenesis remains enigmatic. Here we demonstrate that high iron diet augments the regenerative capacity of Hopx + intestinal stem cells (ISCs) rather than Lgr5 + ISCs to functionally contribute to colon tumor formation. Mechanistically, high iron activates a robust Wnt/β-catenin signaling in ISCs to enhance the proliferation of colonic cells in a Hopx-dependent manner. Furthermore, Wnt/β-catenin induction is attributed to Hopx stabilizing β-catenin protein by directly inhibiting the interaction of β-catenin with UBA52, which targets ubiquitination degradation of β-catenin. This study thus identifies an iron-triggered pathway regulating intestinal tumorigenesis and indicates that iron interventions may complement current prevention and treatment strategies for CRC, and Hopx is a previously unrecognized regulator of β-catenin and a therapeutic target of CRC.