Pan-cancer analysis of the ion permeome reveals functional regulators of glioblastoma aggression

Abstract

ABSTRACT Ion channels, transporters, and other ion-permeating proteins, collectively comprising the ion permeome (IP), are common drug targets. However, their roles in cancer are understudied. Our integrative pan-cancer analysis shows that IP genes display highly-elevated expression patterns in subsets of cancer samples significantly more often than expected transcriptome-wide. To enable target identification, we identified 410 survival-associated IP genes in 29 cancer types using a machine learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived GBM cells induces transcriptome-wide changes involving neural projection and proliferation pathways, impairs cell viability and tumor sphere formation, mitigates tunneling nanotube formation, and extends the survival of GBM-bearing mice. Thus, aberrant activation of IP genes appears as a pan-cancer feature of tumor heterogeneity that can be exploited for mechanistic insights and therapy development.