biostudies-literatureNiu MNational Key R&D Program of ChinaNational Natural Science Foundation of Chinae3001113https://www.ebi.ac.uk/biostudies/studies/S-EPMC7939357biostudies-literatureUnknown19(2)Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-indepePLoS biologyNoncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis.PMC79393572018YFC2000100820732483170124281520108020, 81830108 and 81861148031He TYi YHe YLi FXiao ZJNiu MChen HChen YGGuo RFu MXu JDing LfalseNoncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis.Transforming growth factor-β (TGF-β) signaling plays a critical role in promoting epithelial-to-mesenchymal transition (EMT), cell migration, invasion, and tumor metastasis. ΔNp63α, the major isoform of p63 protein expressed in epithelial cells, is a key transcriptional regulator of cell adhesion program and functions as a critical metastasis suppressor. It has been documented that the expression of ΔNp63α is tightly controlled by oncogenic signaling and is frequently reduced in advanced cancers. However, whether TGF-β signaling regulates ΔNp63α expression in promoting metastasis is largely unclear. In this study, we demonstrate that activation of TGF-β signaling leads to stabilization of E3 ubiquitin ligase FBXO3, which, in turn, targets ΔNp63α for proteasomal degradation in a Smad-indepe2021-01-01T00:00:00Z2021 Feb2025-07-13T03:04:51.172Z2025-07-13T03:04:51.172ZS-EPMC79393573362603510.1371/journal.pbio.3001113