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

Xi Huang, Adrian M. Dubuc, Rintaro Hashizume, Jim Berg, Ye He, Ji Wang, Chin Chiang, Michael K. Cooper, Paul A. Northcott, Michael D. Taylor, Michael J. Barnes, Tarik Tihan, Justin Chen, Christopher S. Hackett, William A. Weiss, C. David James, David H. Rowitch, Marc A. Shuman, Yuh Nung Jan, Lily Yeh Jan

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1780-1796
Number of pages17
JournalGenes and Development
Volume26
Issue number16
DOIs
StatePublished - Aug 15 2012

Keywords

  • Cell cycle
  • Cell volume
  • EAG2
  • Medulloblastoma
  • Mitosis
  • Potassium channel

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Huang, X., Dubuc, A. M., Hashizume, R., Berg, J., He, Y., Wang, J., Chiang, C., Cooper, M. K., Northcott, P. A., Taylor, M. D., Barnes, M. J., Tihan, T., Chen, J., Hackett, C. S., Weiss, W. A., David James, C., Rowitch, D. H., Shuman, M. A., Jan, Y. N., & Jan, L. Y. (2012). Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics. Genes and Development, 26(16), 1780-1796. https://doi.org/10.1101/gad.193789.112