Identification of a Posttranslational Mechanism for the Regulation of hERG1 K⁺ Channel Expression and hERG1 Current Density in Tumor Cells

Abstract

A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K⁺ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (I_hERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher I_hERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

ACKNOWLEDGMENTS

This work was supported in part by funds from the Italian Association for Cancer Research (AIRC) to A.A., the Association for International Cancer Research (AICR) to A.A., the Italian Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MIUR-PRIN-2003054500_006 and MIUR-PRIN-2006053378_002 to A.A.; MIUR-PRIN-2001055320, 2003052919, MIUR-FIRB2001-RBNE01XMP4-002, and MIUR-FISR2001 0300179 to E.W.), the Università di Milano-Bicocca to E.W., and the Ente Cassa di Risparmio di Firenze to A.A. L.G. is a recipient of a fellowship from the Italian Fulbright Commission. E.R. is a postdoc student of physiology at the Department of Biotechnologies and Biosciences of the University of Milan-Bicocca.