ZBTB11 Promotes Breast Cancer Progression by Activating FBXO28‐Mediated MST1 Degradation and Suppressing Hippo Signaling

ABSTRACT Epithelial‐mesenchymal transition (EMT) is a key driver of breast cancer progression, yet the upstream transcriptional and ubiquitin‐mediated mechanisms that modulate Hippo signaling remain incompletely defined. In this study, we identify a regulatory axis in which the transcription factor ZBTB11 promotes breast cancer aggressiveness by enhancing the expression of the F‐box protein FBXO28. ZBTB11 directly binds to the FBXO28 promoter and increases its transcription, leading to elevated FBXO28 protein levels. We show that FBXO28 functions as an E3 ubiquitin ligase that targets the core Hippo kinase MST1 for K48‐linked ubiquitination and proteasomal degradation. Reduction of MST1 diminishes Hippo pathway activity, resulting in decreased phosphorylation and enhanced nuclear accumulation of Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ), which subsequently activates EMT‐related gene expression. Functionally, disruption of the ZBTB11‐FBXO28‐MST1 axis suppresses EMT, migration, invasion, and tumor growth in vitro and in vivo, whereas reintroduction of FBXO28 or depletion of MST1 reverses these effects. Together, our findings reveal a previously unrecognized transcription‐ubiquitination cascade that modulates Hippo signaling and contributes to breast cancer progression, highlighting this axis as a candidate therapeutic vulnerability that warrants further validation for limiting metastasis.