TY - JOUR
T1 - OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-β type I receptor
AU - Fan, Chuannan
AU - Wang, Qian
AU - van der Zon, Gerard
AU - Ren, Jiang
AU - Agaser, Cedrick
AU - Slieker, Roderick C.
AU - Iyengar, Prasanna Vasudevan
AU - Mei, Hailiang
AU - ten Dijke, Peter
N1 - Funding Information: We acknowledge the support of the Chinese Scholarship Council (CSC) to Chuannan Fan and Qian Wang, and the Cancer Genomics Centre in the Netherlands (CGC, NL) and the ZonMW grant (09120012010061) to Peter ten Dijke. We thank Maarten van Dinther and Martijn Rabelink for excellent technical assistance and Slobodan Vukicevic (University of Zagreb, Croatia), and Andrew Hinck (University of Pittsburgh, USA) for generously providing human recombinant BMP6 and TGF-?3, respectively. We acknowledge A.G. Jochemsen for providing the FH1tUTG vector. We are grateful to Midory Thorikay for help with testing effect of compounds on OVOL1 expression and checking the expression of OVOL1 in breast cancer cell lines, Jing Zhang for the help with GSEA, Sijia Liu for instructions on how to perform the zebrafish xenograft assay, and all other members in ten Dijke?s laboratory and Yuva Oz for their kind support. Funding Information: We acknowledge the support of the Chinese Scholarship Council (CSC) to Chuannan Fan and Qian Wang, and the Cancer Genomics Centre in the Netherlands (CGC, NL) and the ZonMW grant (09120012010061) to Peter ten Dijke. We thank Maarten van Dinther and Martijn Rabelink for excellent technical assistance and Slobodan Vukicevic (University of Zagreb, Croatia), and Andrew Hinck (University of Pittsburgh, USA) for generously providing human recombinant BMP6 and TGF-β3, respectively. We acknowledge A.G. Jochemsen for providing the FH1tUTG vector. We are grateful to Midory Thorikay for help with testing effect of compounds on OVOL1 expression and checking the expression of OVOL1 in breast cancer cell lines, Jing Zhang for the help with GSEA, Sijia Liu for instructions on how to perform the zebrafish xenograft assay, and all other members in ten Dijke’s laboratory and Yuva Oz for their kind support. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128890604&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41392-022-00944-w
DO - https://doi.org/10.1038/s41392-022-00944-w
M3 - Article
C2 - 35484112
SN - 2095-9907
VL - 7
JO - Signal Transduction and Targeted Therapy
JF - Signal Transduction and Targeted Therapy
IS - 1
M1 - 126
ER -