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.
An Xu, Xiang-nan Xu, Xiao Huang et al.· Advancement of science· 0 citations
Triple-negative breast cancer (TNBC) represents the most aggressive form of breast cancer and is associated with the worst prognosis. Ferroptosis holds great promise as an emerging therapeutic strategy; however, TNBC cells demonstrate reduced sensitivity to ferroptosis as a result of elevated mitochondrial membrane potential (MMP), inadequate production of reactive oxygen species (ROS), and the presence of activated antioxidant defencses, making it difficult for lipid peroxidation to accumulate to a lethal threshold. As an emerging therapeutic strategy, sonodynamic therapy (SDT) is particularly suitable for deep-seated tumors due to the excellent tissue penetration capabilities of ultrasound (US). Nevertheless, current sonosensitizer typically experience limited sonodynamic efficacy and inadequate targeting of tumors, whereas small interfering RNA (siRNA) presents a highly promising option for gene therapy, its efficacy is heavily dependent on efficient and safe cellular delivery vectors. Therefore, we designed and synthesized a folate-modified Fe-TCPP metal-organic framework (FTFA) nanoplatform that serves both as a siATAD3A gene therapy carrier and as a sonosensitizer to generate ROS upon ultrasound (US) irradiation. ATAD3A displays high expression levels in TNBC and is linked to a negative prognosis; it's silencing reduces MMPs and increases ROS-induced apoptosis. siATAD3A was loaded onto FTFA to prepare FTFA@siATAD3A, which was delivered to TNBC cells via folate receptor-mediated targeting. Under US irradiation, the Fe3+ loaded within this platform synergistically triggers a ferroptosis cascade involving the Fenton reaction, lipid peroxidation, and GPX4 downregulation, effectively inducing ferroptosis. This method greatly reduces the proliferation of cells, as well as their migration and tumor growth when tested in living organisms, and it also shows excellent compatibility with biological tissues. In summary, FTFA@siATAD3A provides a novel strategy for the synergistic gene-ferroptosis therapy of TNBC using sonodynamic effects.
Yang Du, Jiang N. Yang, Shuai Chen et al.· ACS Biomaterials Science & E...· 0 citations
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