YWHAG Deficiency Disrupts the EMT‐Associated Network to Induce Oxidative Cell Death and Prevent Metastasis

Abstract Metastasis involves epithelial‐to‐mesenchymal transition (EMT), a process that is regulated by complex gene networks, where their deliberate disruption may yield a promising outcome. However, little is known about mechanisms that coordinate these metastasis‐associated networks. To address this gap, hub genes with broad engagement across various human cancers by analyzing the transcriptomes of different cancer cell types undergoing EMT are identified. The oncogenic signaling adaptor protein tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein gamma (YWHAG) is ranked top for its clinical relevance and impact. The cellular kinome and transcriptome data are surveyed to construct the regulome of YWHAG, revealing stress responses and metabolic processes during cancer EMT. It is demonstrated that a YWHAG‐dependent cytoprotective mechanism in the regulome is embedded in EMT‐associated networks to protect cancer cells from oxidative catastrophe through enhanced autophagy during EMT. YWHAG deficiency results in a rapid accumulation of reactive oxygen species (ROS), delayed EMT, and cell death. Tumor allografts show that metastasis potential and overall survival time are correlated with the YWHAG expression level of cancer cell lines. Metastasized tumors have higher expression of YWHAG and autophagy‐related genes than primary tumors. Silencing YWHAG diminishes primary tumor volumes, prevents metastasis, and prolongs the median survival period of the mice.