Control of epithelial homeostasis by apical polarity: it takes a network.

The maintenance of cell functions in response to various stimuli is fulfilled by tightly controlled homeostatic processes. The basoapical structure of normal epithelia is increasingly recognized as the guardian of homeostasis. It has recently been demonstrated that apical polarity, depicted by lateroapical tight junctions, is controlled by gap junctions and sets the resting membrane potential, itself essential for homeostasis, in the breast luminal epithelium. In the breast, the disruption of apical polarity is recognized as a necessary step toward cancer onset, which calls for a better understanding of its consequences on the mechanisms of homeostasis all the way to the genome. Here, we extend the traditional apical junctional complex to include gap junctions and investigate its relation with epigenetically- driven and higher order chromatin organization. The disruption of apical polarity affects different types of molecular networks that remodel chromatin with a tendency toward openness or relaxation, a status typically associated with instability and cancer onset. Events known to foster the development of cancers, such as chronic inflammation, oxidative stress, stiffer microenvironment, and aging, are all triggering the disruption of apical polarity, which leads us to explore possibilities to re-establish full polarity. Focusing on gap junction intercellular communication mediated by Connexin 43 might be an interesting therapeutic option for retinoic acid derivatives. However, in light of the different degrees of apical polarity loss, we surmise that the resulting chromatin alterations might depend on the way apical polarity is disrupted initially, which suggests that therapeutic combinations targeted also toward these alterations might be required.