Cancer-associated loss-of-function mutations in KCNQ1 enhance Wnt/β-catenin signalling disrupting epithelial homeostasis

Abstract

Ion channels are emerging as regulators of intracellular signalling pathway, yet the molecular mechanisms underlying this role remain poorly understood. KCNQ1, a potassium channel with tumour suppressor functions, restricts Wnt/β-catenin signalling, a pathway whose dysregulation, often driven by protein-altering mutations, is a hallmark of several epithelial cancers. Here, we identify loss-of-function (LOF) mutations in KCNQ1 across multiple epithelial cancers and elucidate their impact on Wnt/β-catenin signalling. Our findings reveal that cancer-associated KCNQ1-LOF mutations regulate the β-catenin pathway through a dual mechanism. First, they drive β-catenin transcriptional activity through triggering MET receptor, bypassing Frizzled/LRP6 receptor complex activation. Second, these mutations suppress the expression of key negative regulators of Wnt signalling, such as DKK-1, Wif-1 and NKD-1, leading to amplified pathway activation in response to Wnt ligand stimulation. This dysregulation disrupts epithelial homeostasis, as demonstrated by impaired crypt organization and increased proliferation in mouse colon-derived organoids. Together, these findings uncover an original mechanism linking KCNQ1 dysfunction to aberrant Wnt/β-catenin signalling, highlighting the role of ion channels in regulating epithelial signalling networks and tissue homeostasis.