Mechanical cues-induced SKP2 expression mediates YAP-dependent cell cycle exit and oncogenic functions

Abstract

Mechanical tensions are usually generated during development at spatially defined regions within tissues. Such physical cues dictate the cellular decisions of proliferation or cell-cycle arrest. Yet, how mechanical stress controls cell cycle is not fully understood. Here, I report that mechanical cues function upstream of Skp2 transcription. I found that YAP, the mechano-responsive oncogenic Hippo signaling effector, directly promotes Skp2 transcription. YAP inactivation induces cell cycle exit (G0) by down-regulating Skp2, causing p21/p27 to accumulate. Both Skp2 reconstitution and p21/p27 depletion can rescue the observed defect in cell cycle progression. In context of a tissue-mimicking 3D culture system, Skp2 inactivation effectively suppresses YAP-driven oncogenesis and aberrant stiff 3D matrix-evoked epithelial tissue behaviors. Finally, I also found that the expression of Skp2 and YAP are positively correlated in breast cancer patients. My results not only reveal the molecular mechanism by which mechanical cues induce Skp2 transcription, they also uncover a role for YAP-Skp2 oncogenic signaling in the relationship between tissue rigidity and cancer progression.