Abstract 6034: Detection of potassium channel (KCN) gene expression, often multiple and pH sensitive, in cancer genomic landscapes, as low to mid level genes of interest, suggests potassium transmembrane flow may enable proton efflux in a Goldilocks manner
Authors: Beckner Marie E. 
Published: June 2023

A reversed pH gradient across cell membranes underlies multiple malignant features, including invasiveness. Extracellular low pH activates metalloproteases and intracellular high pH activates ATP citrate lyase, inactivates caspases, etc. Hydrogen ions attracted to inner membrane fixed anions are putatively displaced by potassium ion flow through membrane channels. Altered expression of potassium channel (KCN) genes sensitive to pH in invasive brain tumors (Beckner, Proc AACR, A3039, 2022) and 2 mutated KCN genes (1 pH sensitive) in U87 glioblastoma cells (Clark MJ et al, PLOS Genet 2010, e1000832) led to this investigation. Published studies with altered expression or mutations in KCN genes qualifying them as genes of interest (GOI) were compared. Both study types included breast, lung, gastrointestinal, brain, bone marrow, liver, melanocytic malignancies, and 8 others were in either. At least 1 figure (heatmap, Venn diagram, phylogenetic tree, etc.) or table (not Supplemental) had 1 or more KCN genes in a group of GOI. Average numbers of GOI with 95% CI for 23 expression and 14 mutation studies were 38.5 ± 0.4 and 28.4 ± 0.4. No KCN GOI was further examined in the studies. Expression was according to tumor types, inhibitors, siRNAs, regulators of pathways, transcription factors, location, etc. Mutations were single nucleotide polymorphisms, insertions, deletions, fusions, etc. Tissue from surgery, organoids, xenografts, cell lines, stem cells, etc. were analyzed. Of 27 KCN GOI in expression studies, 2/3 were detected with other KCN GOI. For 12 mutated KCN genes there were no other KCN genes mutated in the same study. In expression studies, 8 (34.8%) had multiple KCN GOI, differing from mutation studies, p=0.015, Fishers Exact. In expression studies, 8 found pH sensitive KCN GOI including KCNK1 (2X), K3, K5, K6, K12, K15 (2X), and KCNJ16. In mutation studies, KCNK9 was the only one found. The most frequently mutated KCN subfamily was KCNJ, KCNJ5 (2X) and KCNJ12 (2X). All expression studies included at least 1 repeat GOI (KCN or other). APOE, RET, and RTN1 were each GOI 3 times. Additionally, 40 expressed GOI (including 6 KCN GOI) were found 2X. A small cell lung cancer study had 6 repeats (30%) in 20 GOI (ASCL1, BCL2, KCNA1, RET, SCN3A, and SOX2). KCN gene multiplicity, often pH sensitive members, among low to mid level GOI consistent with a Goldilocks' level of expression, and repeated association with cancer genes supports a pH related measured/regulated role for potassium channels in malignancy. Mainly inward (and some outward for recirculation) potassium transmembrane flows in tumor cells potentially compete with hydrogen ions attracted to inner membrane anions to promote proton efflux by displacement with subsequent reversed pH gradients that aid invasion, cell survival, etc.

Citation Format: Marie E. Beckner. Detection of potassium channel (KCN) gene expression, often multiple and pH sensitive, in cancer genomic landscapes, as low to mid level genes of interest, suggests potassium transmembrane flow may enable proton efflux in a Goldilocks manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6034.