Mechanotransduction at the Crossroads: PIEZO1-Mediated Regulation of YAP and β-Catenin Nuclear Localization

Abstract

Piezo1, a key mechanosensitive ion channel, is fundamental in converting mechanical stimuli into cellular signals through mechanotransduction, impacting essential cellular functions such as proliferation, migration, and survival. Particularly in breast cancer, the implications of Piezo1 on YAP and β-catenin remain underexplored despite their significant roles in regulating cell migration. Our study investigates the effects of Piezo1 on these pathways in MDA-MB-231 breast cancer cells, noting its influence on cancer progression and potential as a therapeutic target.

Our findings reveal that Piezo1 knockdown results in decreased YAP activity and increased nuclear localization of β-catenin. This regulatory effect is reversed by Yoda1 treatment, suggesting that Piezo1 dynamically regulates these processes. Interestingly, this Piezo1-mediated YAP/β-catenin effect is stiffness-dependent. We also discovered that disrupting the actin cytoskeleton decreases nuclear YAP while increasing β-catenin nuclear localization, mirroring the effects of Piezo1 knockdown. Furthermore, Piezo1 knockdown appears to adversely impact the actin cytoskeleton structure. Conversely, inhibiting myosin-II specifically boosts β-catenin nuclear localization without influencing YAP. Together, these findings underscore the critical role of the cytoskeleton in the Piezo1-mediated pathway.

These observations indicate that Piezo1's regulatory effects on YAP and β-catenin are mediated through the actin cytoskeleton. This study reveals the complexity of the Piezo1-mediated mechanotransduction mechanisms in breast cancer, offering insights that could lead to novel mechanistic-based therapeutic strategies for managing breast cancer progression and metastasis.