Emerging roles for multifunctional ion channel auxiliary subunits in cancer

[Display omitted] •Ion channels consist of conducting and non-conducting (auxiliary) subunits.•Auxiliary subunits regulate ion conductance and have non-conducting roles.•Ion channels control diverse cellular processes and are aberrantly expressed in cancer.•Auxiliary subunits play major roles in cancer cells, including regulating adhesion, migration, invasion and gene expression. Several superfamilies of plasma membrane channels which regulate transmembrane ion flux have also been shown to regulate a multitude of cellular processes, including proliferation and migration. Ion channels are typically multimeric complexes consisting of conducting subunits and auxiliary, non-conducting subunits. Auxiliary subunits modulate the function of conducting subunits and have putative non-conducting roles, further expanding the repertoire of cellular processes governed by ion channel complexes to processes such as transcellular adhesion and gene transcription. Given this expansive influence of ion channels on cellular behaviour it is perhaps no surprise that aberrant ion channel expression is a common occurrence in cancer. This review will focus on the conducting and non-conducting roles of the auxiliary subunits of various Ca2+, K+, Na+ and Cl− channels and the burgeoning evidence linking such auxiliary subunits to cancer. Several subunits are upregulated (e.g. Cavβ, Cavγ) and downregulated (e.g. Kvβ) in cancer, while other subunits have been functionally implicated as oncogenes (e.g. Navβ1, Cavα2δ1) and tumour suppressor genes (e.g. CLCA2, KCNE2, BKγ1) based on in vivo studies. The strengthening link between ion channel auxiliary subunits and cancer has exposed these subunits as potential biomarkers and therapeutic targets. However further mechanistic understanding is required into how these subunits contribute to tumour progression before their therapeutic potential can be fully realised.