ABSTRACT

Triple-negative breast cancer (TNBC) is the most aggressive histological subtype of breast cancer and is characterized by poor outcomes and a lack of specific-targeted therapies. Transforming growth factor-β (TGF-β) acts as the key cytokine in the epithelial–mesenchymal transition (EMT) and the metastasis of TNBC. However, the regulatory mechanisms of the TGF-β signaling pathway remain largely unknown. In this study, we identified that the USP1/WDR48 complex could effectively enhance TGF-β-mediated EMT and migration of TNBC cells. Furthermore, lower phosphorylation of Smad2/3, Erk, Jnk, and p38 was noted on the suppression of the expression of endogenous USP1 or WDR48. Moreover, the USP1-WDR48 complex was found to downregulate the polyubiquitination of TAK1 and mediate its in vitro stability. Therefore, our findings have shed a light on the novel role of the USP1/WDR48 complex in promoting TGF-β-induced EMT and migration in TNBC via in vitro stabilization of TAK1.

摘要

三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的组织学亚型，其特点是预后不良且缺乏特异性靶向治疗。转化生长因子-β (TGF-β) 是上皮间质转化 (EMT) 和 TNBC 转移中的关键细胞因子。然而，TGF-β信号通路的调节机制仍然很大程度上未知。在这项研究中，我们发现USP1/WDR48复合物可以有效增强TGF-β介导的EMT和TNBC细胞的迁移。此外，Smad2/3、Erk、Jnk 和 p38 的较低磷酸化会抑制内源性 USP1 或 WDR48 的表达。此外，还发现 USP1-WDR48 复合物可下调 TAK1 的多泛素化并介导其体外稳定性。因此，我们的研究结果揭示了 USP1/WDR48 复合物通过体外稳定 TAK1 促进 TGF-β 诱导的 EMT 和 TNBC 迁移的新作用。