Connexin-mediated regulation of nuclear activity in cancer: Direct and indirect mechanisms

Connexins are classically defined as structural subunits of gap junction channels that mediate direct intercellular communication, and their dysregulation is a recognized feature of many cancers. Growing evidence suggests that connexins can influence cancer by regulating nuclear activity via both gap junction-mediated transfer of signaling molecules and channel-independent functions. However, much of the available evidence remains observational, and the mechanisms underlying these transcriptional effects are incompletely understood. More recent studies have begun to address this gap, including work showing that connexins can localize to the nucleus and directly influence gene expression. In this review, we examine current evidence that connexins regulate nuclear activity in cancer, addressing both tumor-promoting and tumor-suppressive functions. We discuss how gap junctional intercellular communication influences nuclear activity through the exchange of ions and signaling molecules and distinguish these effects from those mediated by connexin protein interactions, scaffold functions, and the nuclear or perinuclear localization of connexins or their truncated isoforms. We propose that connexins integrate intercellular communication with intracellular signaling to shape nuclear regulatory programs in a context-dependent manner, and we highlight the key challenges that must be addressed before these mechanisms can be fully understood and therapeutically targeted.