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

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.

• Authors: Michelle A Francisco, Siyi Wanggou, Jerry J Fan, Weifan Dong, Xin Chen, Ali Momin, Namal Abeysundara, Hyun-Kee Min, Jade Chan, Rochelle McAdam, Marian Sia, Ronwell J Pusong, Shixuan Liu, Nish Patel, Vijay Ramaswamy, Noriyuki Kijima, Lu-Yang Wang, Yuanquan Song, Ran Kafri, Michael D Taylor, Xuejun Li, Xi Huang
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 217 Issue 5 (05 04 2020) ISSN: 1540-9538 [Electronic] United States
• PMID: 32097463 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2020 Francisco et al.

Chemical References

• CLIC1 protein, human
• Chloride Channels
• Drosophila Proteins
• Ether-A-Go-Go Potassium Channels
• KCNH5 protein, human
• KCNT2 protein, human
• Potassium Channels, Sodium-Activated
• RNA
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Body Weight
• Cell Line, Tumor
• Cell Proliferation
• Cell Size
• Chloride Channels (deficiency, genetics, metabolism)
• Drosophila Proteins (metabolism)
• Drosophila melanogaster (metabolism)
• Ether-A-Go-Go Potassium Channels (metabolism)
• Gene Knockdown Techniques
• Homeostasis
• Medulloblastoma (metabolism, pathology)
• Mice
• Mitosis
• Mutation (genetics)
• Potassium Channels, Sodium-Activated (metabolism)
• Protein Binding
• RNA (biosynthesis)
• Survival Analysis
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (metabolism)