Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis. Cell Rep 2025 Sep 23;44(9):116303
Date
09/14/2025Pubmed ID
40946315Pubmed Central ID
PMC12443334DOI
10.1016/j.celrep.2025.116303Scopus ID
2-s2.0-105015763810 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
The coordination of cellular processes such as growth and survival relies on communication between cells through gap junctions. Connexin proteins comprise gap junctions and also function to mediate protein-protein interactions and communication with the extracellular space via hemichannels. Despite their essential roles, connexin function in cancer is context dependent, with connexin 43 (Cx43) reported to both promote and suppress tumor growth in glioblastoma, the most common primary malignant brain tumor. Here, we detect primarily intracellular expression of Cx43 in glioblastoma patient-derived cancer stem cells and demonstrate that Cx43 is essential for their survival, self-renewal, and tumor initiation. Mechanistically, Cx43 depletion reduces c-MYC expression through reduced levels of the upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). WNK1 depletion phenocopies Cx43 knockdown and reduces c-MYC expression and tumor initiation. Together, these results define a signaling axis downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in glioblastoma.
Author List
Mulkearns-Hubert EE, Hajdari N, Hong ES, Jacobs AP, Gaboriau A, Giltner S, Tannish G, Kay KE, Wang SZ, LaViolette PS, Silver DJ, Hubert CG, Dhawan A, Lathia JDAuthor
Peter LaViolette PhD Vice Chair, Professor in the Radiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain Neoplasms
Cell Line, Tumor
Cell Proliferation
Connexin 43
Gap Junctions
Glioblastoma
Humans
Mice
Neoplastic Stem Cells
Phenotype
Proto-Oncogene Proteins c-myc
Signal Transduction
WNK Lysine-Deficient Protein Kinase 1
