OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-β type I receptor.

Autor: Fan C; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Wang Q; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., van der Zon G; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Ren J; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Agaser C; Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Slieker RC; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.; Department of Epidemiology and Data Science, Amsterdam Public Health Institute, Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, location VUmc, Amsterdam, 1081 HV, The Netherlands., Iyengar PV; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Mei H; Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands., Ten Dijke P; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands. p.ten_dijke@lumc.nl.; Oncode Institute, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands. p.ten_dijke@lumc.nl.
Jazyk: angličtina
Zdroj: Signal transduction and targeted therapy [Signal Transduct Target Ther] 2022 Apr 29; Vol. 7 (1), pp. 126. Date of Electronic Publication: 2022 Apr 29.
DOI: 10.1038/s41392-022-00944-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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