KCNQ gene family members act as both tumor suppressors and oncogenes in gastrointestinal cancers

Shorthouse, D.; Rahrmann, E.; Kosmidou, C.; Greenwood, B.; Hall, M. W. J.; Devonshire, G.; Gilbertson, R.; Fitzgerald, R.; Hall, B. A.

doi:10.1101/2020.03.10.984039

bioRxiv · 10.1101/2020.03.10.984039

KCNQ gene family members act as both tumor suppressors and oncogenes in gastrointestinal cancers

Shorthouse, D.·Rahrmann, E.·Kosmidou, C.·Greenwood, B.·Hall, M. W. J.·Devonshire, G.·Gilbertson, R.·Fitzgerald, R.·Hall, B. A.

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Abstract

Voltage sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large scale analysis of 1594 patients with GI cancers coupled with in vitro models we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GI cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation, and its resultant effects on cadherins junctions. This also highlights novel roles for KCNQ3 in non-excitable tissues. We additionally discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors, and that inhibition of KCNQ activity reduces proliferation of GI cancer. These findings reveal a novel and exploitable role for potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GI cancers may exist through KCNQ inhibitors. SIGNIFICANCEKCNQ channels modulate the WNT pathway and MYC signalling, and drive growth of gastrointestinal cancers. Available drugs modulate these pathways and offer therapeutic potential in gastrointestinal cancer.

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Shorthouse, D., Rahrmann, E., Kosmidou, C., Greenwood, B., Hall, M. W. J., Devonshire, G., Gilbertson, R., Fitzgerald, R., Hall, B. A.. 2020-03-10. KCNQ gene family members act as both tumor suppressors and oncogenes in gastrointestinal cancers. https://doi.org/10.1101/2020.03.10.984039

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