OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-β type I receptor.
Chuannan FanQian WangGerard van der ZonJiang RenCedrick AgaserRoderick C SliekerPrasanna Vasudevan IyengarHailiang MeiPeter Ten DijkePublished in: Signal transduction and targeted therapy (2022)
Ovo-like transcriptional repressor 1 (OVOL1) is a key mediator of epithelial lineage determination and mesenchymal-epithelial transition (MET). The cytokines transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMP) control the epithelial-mesenchymal plasticity (EMP) of cancer cells, but whether this occurs through interplay with OVOL1 is not known. Here, we show that OVOL1 is inversely correlated with the epithelial-mesenchymal transition (EMT) signature, and is an indicator of a favorable prognosis for breast cancer patients. OVOL1 suppresses EMT, migration, extravasation, and early metastatic events of breast cancer cells. Importantly, BMP strongly promotes the expression of OVOL1, which enhances BMP signaling in turn. This positive feedback loop is established through the inhibition of TGF-β receptor signaling by OVOL1. Mechanistically, OVOL1 interacts with and prevents the ubiquitination and degradation of SMAD family member 7 (SMAD7), which is a negative regulator of TGF-β type I receptor stability. Moreover, a small-molecule compound 6-formylindolo(3,2-b)carbazole (FICZ) was identified to activate OVOL1 expression and thereby antagonizing (at least in part) TGF-β-mediated EMT and migration in breast cancer cells. Our results uncover a novel mechanism by which OVOL1 attenuates TGF-β/SMAD signaling and maintains the epithelial identity of breast cancer cells.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- breast cancer cells
- signaling pathway
- small molecule
- mesenchymal stem cells
- transcription factor
- poor prognosis
- stem cells
- binding protein
- small cell lung cancer
- bone regeneration
- bone marrow
- gene expression
- squamous cell carcinoma
- long non coding rna
- bone mineral density
- mouse model
- high resolution
- solid phase extraction
- postmenopausal women
- protein protein
- quantum dots