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.
Signal Transduct Target Ther. 2022 Apr 29;7(1):126. doi: 10.1038/s41392-022-00944-w.
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.
卵黄样转录抑制因子 1（OVOL1）是上皮谱系决定和间质-上皮转化（MET）的关键介质。转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）等细胞因子控制着癌细胞的上皮-间充质可塑性（EMP），但它们是否通过与 OVOL1 的相互作用来实现这一点尚不清楚。在这里，我们表明 OVOL1 与上皮-间充质转化（EMT）标志物呈负相关，并且是乳腺癌患者预后良好的指标。OVOL1 抑制 EMT、迁移、外渗和乳腺癌细胞的早期转移事件。重要的是，BMP 强烈促进 OVOL1 的表达，从而增强 BMP 信号。这种正反馈环是通过 OVOL1 抑制 TGF-β 受体信号来建立的。在机制上，OVOL1 与 SMAD 家族成员 7（SMAD7）相互作用，并阻止其泛素化和降解，SMAD7 是 TGF-β 型 I 受体稳定性的负调节剂。此外，还鉴定出一种小分子化合物 6-甲酰基吲哚并[3,2-b]咔唑（FICZ），它可以激活 OVOL1 的表达，从而拮抗（至少部分拮抗）TGF-β 介导的乳腺癌细胞 EMT 和迁移。我们的研究结果揭示了 OVOL1 减弱 TGF-β/SMAD 信号并维持乳腺癌细胞上皮特性的新机制。
