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

Author:

Bahcheli Alexander T.,Min Hyun-Kee,Bayati Masroor,Dong Weifan,Fortuna Alexander,Zhao Hongyu,Dzneladze Irakli,Chan Jade,Chen Xin,Guevara-Hoyer Kissy,Dirks Peter B.,Huang Xi,Reimand Jüri

Abstract

ABSTRACTIon 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,GJB2andSCN9Ashow prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer.GJB2orSCN9Aknockdown 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.

Publisher

Cold Spring Harbor Laboratory

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