Cyclic expression of the voltage‐gated potassium channel K_V10.1 promotes disassembly of the primary cilium

Abstract

The primary cilium, critical for morphogenic and growth factor signaling, is assembled upon cell cycle exit, but the links between ciliogenesis and cell cycle progression are unclear. KV10.1 is a voltage‐gated potassium channel frequently overexpressed in tumors. We have previously reported that expression of KV10.1 is temporally restricted to a time period immediately prior to mitosis in healthy cells. Here, we provide microscopical and biochemical evidence that KV10.1 localizes to the centrosome and the primary cilium and promotes ciliary disassembly. Interference with KV10.1 ciliary localization abolishes not only the effects on ciliary disassembly, but also KV10.1‐induced tumor progression in vivo. Conversely, upon knockdown of KV10.1, ciliary disassembly is impaired, proliferation is delayed, and proliferating cells show prominent primary cilia. Thus, modulation of ciliogenesis by KV10.1 can explain the influence of KV10.1 expression on the proliferation of normal cells and is likely to be a major mechanism underlying its tumorigenic effects.

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

“…It was believed that K v 10.1 is only present in the central nervous system, but its expression becomes significantly elevated in up to 80% of human tumors (206). Recent data, however, show that K v 10.1 is also present in healthy cells, but its expression is temporally restricted to a premitotic period in which its activity is important for ciliary disassembly (437). Oncogenic potential of K v 10.1 was proven by a variety of approaches in a number of experimental and clinical models, including channel overexpression and silencing in primary cancer cells and cell lines, xenograft tumors, and human cancer tissue biopsies (reviewed in Ref.…”

“…Since pRb/ E2F1 complex is disrupted in cancer, this explains why K v 10.1 is often upregulated in cancer cell lines and clinical tumor specimens (495). In normal cells, K v 10.1 expression during G 2 /M phases was shown to promote ciliary disassembly which is required for cells to divide (437). The latter effect involved K v 10.1 K ϩ permeation, suggesting that it could be associated with local hyperpolarization of the primary cilium (437).…”

Ether‐à‐go‐go K+ channels: effective modulators of neuronal excitability

“…Indeed, in mouse embryonic fibroblasts, expression of an eag1 channel mutant identified in a Zimmermann–Laband patient enhanced the effect of eag1 on ciliary resorption (Sánchez et al . ). Patients with KCNH1 mutations can suffer from different seizure types (Mastrangelo et al .…”

Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

“…At this point, we cannot rule out that ion flow through Kv10.1 is only a part of the signaling mechanism. Active Kv10.1 channels participate in primary cilium disassembly [16,43], a process that is also impaired by mitochondrial stress [44]. Both ciliary homeostasis [45] and mitochondrial dynamics [46] require calcium signaling, and active potassium channels hyperpolarize the membrane, increasing the driving force for calcium to enter the cells.…”