RESEARCH ARTICLE Inhibitory Mechanism of FAT4 Gene Expression in Response to Actin Dynamics

Oncogenic transformation is characterized by morphological changes resulting from alter-ations in actin dynamics and adhesive activities. Emerging evidence suggests that the pro-tocadherin FAT4 acts as a tumor suppressor in humans, and reduced FAT4 gene expression has been reported in breast and lung cancers and melanoma. However, the mechanism controlling FAT4 gene expression is poorly understood. In this study, we show that transient activation of the Src oncoprotein represses FAT4mRNA expression through actin depolymerization in the immortalized normal human mammary epithelial cell line MCF-10A. Src activation causes actin depolymerization via the MEK/Erk/Cofilin cascade. The MEK inhibitor U0126 blocks the inhibitory effect of Src on FAT4mRNA expression and Src-induced actin depolymerization. To determine whether actin dynamics act on the regulation of FAT4mRNA expression, we treated MCF-10A cells with the ROCK inhibitor Y-27632. Y-27632 treatment decreased FAT4mRNA expression. This suppressive effect was blocked by siRNA-mediated knockdown of Cofilin1. Furthermore, simultaneous admin-istration of Latrunculin A (an actin depolymerizing agent), Y-27632, and Cofilin1 siRNA to the cells resulted in a marked reduction of FAT4mRNA expression. Intriguingly, we also found that FAT4mRNA expression was reduced under both low cell density and low stiff-ness conditions, which suggests that mechanotransduction affects FAT4mRNA expres-sion. Additionally, we show that siRNA-mediated FAT4 knockdown induced the activity of the Hippo effector YAP/TAZ in MCF-10A cells. Taken together, our results reveal a novel in-hibitory mechanism of FAT4 gene expression through actin depolymerization during Src-induced carcinogenesis in human breast cells