Ion Channel Activity Promotes Mitotic Entry and Tumor Cell Growth

Medulloblastomas are classified into 4 distinct subgroups— SHH, WNT, group 3, and group 4—based on their clinical, biologic, and genetic profiles. Actionable targets have not yet been identified for WNT, group 3, and group 4 tumors, which represent approximately three quarters of all medulloblastomas. Overexpression or amplification of ion channels, which are abundant in the central nervous system, has been observed in several cancers, but the contributions of ion channels to tumorigenesis are unclear. Huang and colleagues performed genome-wide expression analysis on mouse medulloblastomas and observed that ether-a-go-go-related potassium channel 2 (Eag2) was the most highly upregulated ion channel gene in medulloblastomas relative to normal cerebellum. An analysis of 4 independent cohorts of human medulloblastomas further revealed that EAG2 was overexpressed in a sizable subset of tumors representing multiple clinical subgroups. Knockdown of EAG2 in primary medulloblastoma cells inhibited cell growth in vitro and significantly improved the survival of tumor-bearing mice. The authors noted that EAG2 shuttles to the plasma membrane in late G₂ phase and remains there throughout mitosis, suggesting that the impaired cell growth caused by EAG2 loss might be due to defects in mitotic entry. Indeed, EAG2 knockdown in medulloblastoma cells led to G₂ arrest and mitotic catastrophe associated with aberrant premitotic cytoplasmic condensation. EAG2 depletion led to a striking increase in cell volume in late G₂ that activated a p38 MAP kinase–mediated hypotonic stress response required for cell-cycle arrest, providing a potential explanation for the reduced tumorigenicity of EAG2-deficient medulloblastoma cells. These findings thus suggest that EAG2 overexpression in medulloblastoma may accommodate the frequent changes in cell volume required for rapid cell proliferation and implicate the EAG2 voltage-gated potassium channel as a potentially druggable therapeutic target in a subset of medulloblastomas.

Huang X, Dubuc AM, Hashizume R, Berg J, He Y, Wang J, et al. Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics. Genes Dev 2012;26:1780–96.

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