Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
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Archivos
Fecha
2025-12
Profesor/a Guía
Facultad/escuela
Idioma
en
Título de la revista
ISSN de la revista
Título del volumen
Editor
BioMed Central Ltd
Nombre de Curso
Licencia CC
Attribution-NonCommercial-NoDerivatives 4.0 International
Licencia CC
https://creativecommons.org/licenses/by-nc-nd/4.0/
Resumen
Background Oncogenes drive cancer progression, but few are active exclusively in tumor cells. Connexins (Cxs),
traditionally recognized as ion channel proteins, can localize to the nucleus and regulate gene expression, playing key
roles in both physiological and pathological processes. Cx46, once thought to be restricted to the eye lens, has been
implicated in tumor growth, though its underlying mechanisms remain unclear. This study investigates the nuclear
presence of Cx46 in cancer cells and its potential role as a transcriptional modulator.
Methods We employed ChIP-Seq, confocal immunofuorescence, and nuclear protein purifcation to assess Cx46
localization and DNA interactions. Functional assays were conducted to evaluate its efects on invasion, division, spheroid formation, and mesenchymal marker expression. Single-point mutations and molecular dynamics simulations
were used to explore potential Cx46-DNA interactions.
Results Cx46 mRNA upregulation was found in a variety of tumors compared to adjacent healthy tissue. In HeLa
cells, which do not express Cx46, its transfection promoted proliferation, invasion and self-renewal capacity, cancer stem cell traits and mesenchymal features. Consistently, in Sk-Mel-2, which naturally express Cx46, reduced
Cx46 expression led to a decrease in the similar parameters. In HeLa cells, nuclear Cx46 was detected in two forms,
full length 46 kDa and a 30 kDa fragment (GJA3-30 k), ChIP-Seq experiments revealed that Cx46 binds to the DNA
at intergenic and promoter regions, leading to the activation of oncogenic pathways. Molecular dynamics simulations
suggest that GJA3-30 k dimerizes in a RAD50-like structure, forming stable DNA complexes. Cx46 and in some cases
GJA3-30 k were detected in the nuclei of multiple cancer cell lines, including prostate, breast and skin cancers.
Conclusions Our fndings reveal a novel nuclear role for Cx46 in cancer, demonstrating its function as a transcriptional regulator and its potential as a therapeutic target
Notas
Indexación: Scopus
Palabras clave
Connexin46, Transcription factor, Cancer, IRES
Citación
Cell Communication and Signaling Volume 23, Issue 1 December 2025 Article number 153
DOI
10.1186/s12964-025-02151-w