Abstract 6655: Meta-analysis of 70 cancer studies suggests altered pH-sensitive potassium channeling associated with 7 oncogenes and/or DNA modifiers as initiators of pH reversal via cytosolic proton chains
Authors: Marie E. Beckner
Journal: Cancer Research (2025)

Abstract The potassium channel (KCN) gene family (≥ 90 members) is influenced by upstream modifiers and encodes interactive proteins, many also pH-sensitive. Regulated KCN proteins channel K+flux to mediate optimal K+levels in cells. Small monovalent cations, preferentially K+, can displace protons from inner cell membrane anions. Released free protons rapidly become hydronium ions (H3O+) that react with a "Grotthuss" type water matrix of H-bonded chains of H9O4 + &amp; H5O2 +in a "microaqueous proton chain" (MAPC) cytosol. The chains undergo domino-like conformational changes involving H+that permit protons entering the matrix to incite quick release of different H+elsewhere from matrix edges (Adelroth P, BBA, 1757(2006)867-70). Putatively, elevated release of H+ from cytosolic MAPC near cell exit sites (transporters of H+, etc.) allows pH reversal. Methods. Meta-analysis was performed on cancer studies selected for published gene expression landscapes (not Supplemental Materials), that lacked KCN bias yet yielded differentially expressed genes (DEG) of the KCN family to determine the proportion of KCN DEG affecting pH-sensitive K+flux and to identify associated non-KCN DEG. Heat maps (46 studies), Venn diagrams, tables, phylogenetic trees, etc. were analyzed for count data &amp; with Fisher's Exact testing. Results &amp; Discussion. Thus far in 70 expression (E) studies, E1-E70 (1301 authors), of 29 malignancy types, of the 53 KCN DEG detected, 33 (62.3%) encode H+-sensitive proteins (135 literature references). 52 of 70 studies (74.3%) contained≥1 KCN DEG encoding H+-sensitive proteins. The most frequent KCN DEG, KCNN4 and KCNMA1 in 9 and 6 studies, respectively, encode H+-sensitive proteins. The most common cancers, lung, breast, &amp; glioblastoma, had KCN DEG encoding H+-sensitive proteins detected in 72.7%, 44.4%, &amp; 85.7% of their respective studies. Also, 50 of 70 studies were in 8 author-designated categories which had relevant DEG present in≥1 study. Categories in decreasing frequency are Histone/Chromatin/Epigenetic, TP53, Epithelial Mesenchymal(Mes) Transition/TGFβ/Mes, EGFR, MYC, RAS, BCL2, &amp; MET. Studies in the 8 categories compared to the other 20 studies differed significantly for detection of KCN DEG encoding H+-sensitive proteins, p = 0.0325. Conclusion. Collectively, malignant gene expression landscapes involving 7 oncogenes and/or DNA modifier scenarios are associated with KCN DEGs encoding H+-sensitive proteins, possibly as downstream effectors. Potentially, dysregulated inner membrane K+levels result in release of membrane-bound protons that (1) incite rapid domino-like proton shifts in a MAPC cytosol resulting in proton release elsewhere for (2) enhanced H+ efflux achieving (3) pH reversal causing enhanced malignancy via altered enzyme activities, cytoskeletal rearrangements, etc. Citation Format: Marie E. Beckner. Meta-analysis of 70 cancer studies suggests altered pH-sensitive potassium channeling associated with 7 oncogenes and/or DNA modifiers as initiators of pH reversal via cytosolic proton chains [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6655.