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.

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

“…This suggests the existence of a tumor typerelated hERG1 isoform signature; (ii) hERG1A overexpression in gastric cancer correlates with an increased stability of the corresponding mRNA, in highly hERG1 expressing gastric cancer cells, a fact that candidates this as the mechanism underlying hERG1A overexpression in gastric cancer samples. Consistently, we excluded a significant contribution to hERG1 overexpression by the methylation status of the hERG1A promoters as well as of posttranslational mechanisms, based on the expression of the USO transcripts (20).…”

“…The relevance of posttranslational mechanisms was excluded, because no differences in the amount of the hERG1 USO protein (ref. 20; e.g., the main posttranslational mechanism affecting hERG1 protein levels) were detected ( Supplementary Fig. S5).…”

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

“…To better distinguish these mechanisms, we expressed several mutant constructs in HEK cells: the nonconducting hERG1-G628S (38), hERG1-R531C, and hERG1-K525C, which are S4 domain mutants with altered activation (39), and the noninactivating hERG1-S620T (40). Flow cytometry analysis (41) indicated that the plasma membrane abundance of the mutants was~25 to 30% less compared to that of wild-type hERG1 (Fig. 4C).…”

Arsenic trioxide inhibits breast cancer cell growth via microRNA-328/hERG pathway in MCF-7 cells

“…The human ether-à-go-go-related gene (hERG) is expressed in a number of tumor cell lines of various histogenetic origins, although is not present in the corresponding healthy cells, which indicates an association between hERG expression and the development of cancer (10)(11)(12). In a previous study by this group, it was identified that As 2 O 3 induces the apoptosis of MCF-7 breast cancer cells via inhibition of hERG channels (13).…”