TY - JOUR
T1 - KCNQ potassium channels modulate Wnt activity in gastro-oesophageal adenocarcinomas
AU - Shorthouse, David
AU - Kosmidou, Cassandra
AU - Rahrmann, Katherine Wickham
AU - Hall, Michael
AU - Greenwood, Benedict
AU - Devonshire, Ginny
AU - Gilbertson, Richard J.
AU - Fitzgerald, Rebecca C.
AU - Hall, Benjamin A.
AU - Zhuang, Lizhe
AU - Rahrmann, Eric P.
N1 - Publisher Copyright:
© 2023 Shorthouse et al.
PY - 2023
Y1 - 2023
N2 - 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 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.
AB - 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 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors.
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U2 - 10.26508/lsa.202302124
DO - 10.26508/lsa.202302124
M3 - Article
C2 - 37748809
AN - SCOPUS:85174080569
SN - 2575-1077
VL - 6
JO - Life science alliance
JF - Life science alliance
IS - 12
M1 - e202302124
ER -
