Abstract
Kv10.1 (potassium voltage-gated channel subfamily H member 1, known as EAG1 or Ether-à-go-go 1), is a voltage-gated potassium channel, prevailingly expressed in the central nervous system. The aberrant expression of Kv10.1 is detected in over 70% of all human tumor tissues and correlates with poorer prognosis. In peripheral tissues, Kv10.1 is expressed almost exclusively during the G2/M phase of the cell cycle and regulates its progression—downregulation of Kv10.1 extends the duration of the G2/M phase both in cancer and healthy cells. Here, using biochemical and imaging techniques, such as live-cell measurements of microtubule growth and of cytosolic calcium, we elucidate the mechanisms of Kv10.1-mediated regulation at the G2/M phase. We show that Kv10.1 has a dual effect on mitotic microtubule dynamics. Through the functional interaction with ORAI1 (calcium release-activated calcium channel protein 1), it modulates cytosolic calcium oscillations, thereby changing microtubule behavior. The inhibition of either Kv10.1 or ORAI1 stabilizes the microtubules. In contrast, the knockdown of Kv10.1 increases the dynamicity of mitotic microtubules, resulting in a stronger spindle assembly checkpoint, greater mitotic spindle angle, and a decrease in lagging chromosomes. Understanding of Kv10.1-mediated modulation of the microtubule architecture will help to comprehend how cancer tissue benefits from the presence of Kv10.1, and thereby increase the efficacy and safety of Kv10.1-directed therapeutic strategies.
Highlights
IntroductionKv10.1 (potassium voltage-gated channel subfamily H member 1, known as Ether-à-go-go1, EAG1; encoded by the KCNH1 gene) is a voltage-gated potassium channel [1] almost exclusively expressed in the mammalian central nervous system [2], where it regulates neuronal excitability at high stimulus frequencies [3]
Kv10.1 is a voltage-gated potassium channel [1] almost exclusively expressed in the mammalian central nervous system [2], where it regulates neuronal excitability at high stimulus frequencies [3]
We have previously shown that, in non-neural cells, Kv10.1 localizes to the centrosomes and primary cilia [21], and that its expression occurs only during the G2/M phase of the cell cycle [22]
Summary
Kv10.1 (potassium voltage-gated channel subfamily H member 1, known as Ether-à-go-go1, EAG1; encoded by the KCNH1 gene) is a voltage-gated potassium channel [1] almost exclusively expressed in the mammalian central nervous system [2], where it regulates neuronal excitability at high stimulus frequencies [3]. The functional conservation from cnidarians to humans [4] suggests that Kv10.1 may serve other functions. Kv10.1 was among the early examples of potassium channels implicated in tumor progression. It increases the growth and aggressiveness of implanted tumors in mice [5]. Over 70% of solid human tumors are Kv10.1-positive, which correlates with an unfavorable prognosis [5,6,7,8,9,10,11,12,13,14]. The molecular mechanisms by which Kv10.1 favors cell proliferation and enhances tumor progression are poorly understood
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