Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

Abstract

Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

“…The aberrant expression of ion channels, often absent from healthy tissue, participates to hallmarks of cancer by tuning membrane potential, calcium homeostasis, or signaling pathways (1)(2)(3)(4)(5). For example, KCNH2 (human ether-a-go-go-related gene, hERG), a voltage-dependent K þ channel mainly involved in cardiac activity (6), has been characterized as a biomarker of many solid tumors (colorectal cancer, glioblastoma, head and neck cancers; refs.…”

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels

“…Although it has been proposed for many years that K 1 conduction is important for changes in membrane potential during cell-cycle progression, or for regulation of cell volume in proliferating cells, it is clear that not all members of the K 1 channel superfamily can support these roles. Only a select group of K 1 channels [K v 1.3, K 2P 9.1, human ether-à-go-go (hEAG1), hEAG2, hERG1)] influence proliferation and have been linked to cancer (Bianchi et al, 1998;Pardo et al, 1999;Fraser et al, 2003;Pei et al, 2003;Preussat et al, 2003;Tajima et al, 2006;Huang et al, 2012), suggesting that channel properties other than K 1 selectivity are important. Intriguingly, of this small group, hERG1, hEAG1, and hEAG2 belong to the same subfamily and are closely related.…”

Targeting potassium channels in cancer

“…Conversely, overexpressing EAG2 in heterologous systems (HEK293 and COS7 cells) results in constitutive membrane localization of EAG2 and sustained cell volume reduction, which also impairs cell cycle progression and leads to apoptosis (Huang et al, 2012). Taken together, these results demonstrate that EAG2 regulates cell volume dynamics important for cell cycle progression.…”

“…Interestingly, the regulated potassium channel activity is correlated with a membrane potential oscillation, in which the cell is more depolarized at S and G2 (Day et al, 1993). Since then the cell cycle phase-dependent potassium channel expression, localization, and activity have been found in multiple cell types (Takahashi et al, 1993;Arcangeli et al, 1995;Brüggemann et al, 1997;Ouadid-Ahidouch et al, 2004;Huang et al, 2012), which suggests that it may be a general phenomenon that accompanies proliferation. How does a potassium channel regulate cell cycle progression?…”

“…Whether the potassium channel is required and the physiological significance of this depolarization at G2-M transition remain unclear. (2) Modified from Huang et al (2012): Potassium channels can regulate cell proliferation via controlling cell volume dynamics throughout the cell cycle. This is exemplified by the voltage-gated potassium channel EAG2 that exhibits cell cycle phase-specific membrane localization.…”