Elucidating the function of the potassium channel KCNQ1 in the homeostasis of colonic crypts

In recent years, the role of ion channels in cancer processes has emerged and the field continues to expand. It has been shown that 1) the expression of certain ion channels is deregulated in cancers, and 2) ion channels can regulate various signalling pathways. In physiology, the balance of signalling pathways must be maintained. In the epithelium of the colon, maintaining this balance is particularly crucial as cells undergo rapid renewal which relies on the combined action of multiple signalling pathways. Dysregulated activation of the Wnt/β-catenin signalling pathway, promoting cell proliferation, is a major driver of tumour development in the colon. In most cases of colorectal cancer, patients harbour mutations on the component of this pathway, contributing to its overactivation. The potassium channel KCNQ1 has diverse functions. In the colonic epithelium, it enables water secretion and maintains epithelial integrity by exerting its tumour suppressor activity through the repression of the Wnt/β-catenin pathway. Despite the impact of somatic mutations in cancers, there are no studies, to this day, exploring mutations of ion channels in this context. Therefore, we hypothesized that colorectal cancer patients carry pathogenic mutations on KCNQ1. By analysing publicly available databases, we identified 36 different mutations harboured by KCNQ1 in various cancers. We found that the most common mutations were loss-of-function. In colorectal cancer cells, the loss-of-function mutations were associated with increased Wnt/β-catenin pathway activity, independently of the canonical pathway receptors. We also observed an activation of several tyrosine kinase receptors that could directly mediate β-catenin activation. In the more physiological model of murine colonoids, loss-of-function mutations in KCNQ1 also seem to increase Wnt/β-catenin pathway activity. Furthermore, these mutations had an impact on the expression of Wnt/β-catenin pathway regulators, favouring a permissive state for the pathway overactivation. KCNQ1 thus appears to restrict the signalling pathway at multiple levels: directly by sequestering β-catenin at adherens junctions, preventing its activity as a transcription factor, and indirectly by allowing the expression of regulatory proteins that inhibit the Wnt/β-catenin pathway. Our results highlight, for the first time, that ion channels can carry somatic mutations in cancers, altering channel function. Moreover, our findings demonstrate that these mutations directly influence the activity of signaling pathways involved in cancer processes. Additionally, given that KCNQ1 expression levels can be used for classifying colorectal cancers, these mutations could potentially aid in the prognosis and stratification of patients. Altogether, these findings open a new avenue of investigations to better understand the diversity of mechanisms involved in cancer processes. Numerous other ion channels or their associated subunits may carry somatic mutations in cancers, deregulating their activity and the processes they govern.