Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Author(s) Francisco, M.A.; Wanggou, S.; Fan, J.J.; Dong, W.; Chen, X.; Momin, A.; Abeysundara, N.; Min, H.K.; Chan, J.; McAdam, R.; Sia, M.; Pusong, R.J.; Liu, S.; Patel, N.; Ramaswamy, V.; Kijima, N.; Wang, L.Y.; Song, Y.; Kafri, R.; Taylor, M.D.; Li, X.; Huang, X.
Journal J Exp Med
Date Published 2020 May 04
Abstract

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

DOI 10.1084/jem.20190971
ISSN 1540-9538
Citation Francisco MA, Wanggou S, Fan JJ, Dong W, Chen X, Momin A, et al. Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth. J Exp Med. 2020;217(5).

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