title: 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.
authors.affiliation: Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Jim
authors.initials: J
authors.lastname: Berg
authors.forename: Ye
authors.initials: Y
authors.lastname: He
authors.forename: Ji
authors.initials: J
authors.lastname: Wang
authors.forename: Chin
authors.initials: C
authors.lastname: Chiang
authors.forename: Michael K
authors.initials: MK
authors.lastname: Cooper
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hackett
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Marc A
authors.initials: MA
authors.lastname: Shuman
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
mesh_terms: D000818:Animals; D019556:COS Cells; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008527:Medulloblastoma / Q000401:mortality / Q000503:physiopathology*; D051379:Mice; D008938:Mitosis; D016019:Survival Analysis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels