USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1

Dianwen Han; Lijuan Wang; Bing Chen; Wenjing Zhao; Yiran Liang; Yaming Li; Hanwen Zhang; Ying Liu; Xiaolong Wang; Tong Chen; Chen Li; Xiaojin Song; Dan Luo; Zheng Li; Qifeng Yang

doi:10.1080/15384101.2021.1874695

USP1-WDR48 deubiquitinase complex enhances TGF-β induced epithelial-mesenchymal transition of TNBC cells via stabilizing TAK1

Cell Cycle. 2021 Feb;20(3):320-331. doi: 10.1080/15384101.2021.1874695. Epub 2021 Jan 18.

Authors

Dianwen Han¹, Lijuan Wang², Bing Chen², Wenjing Zhao², Yiran Liang¹, Yaming Li¹, Hanwen Zhang¹, Ying Liu¹, Xiaolong Wang¹, Tong Chen¹, Chen Li¹, Xiaojin Song¹, Dan Luo¹, Zheng Li¹, Qifeng Yang^{1

2

3}

Affiliations

¹ Department of Breast Surgery, Qilu Hospital of Shandong University , Jinan, China.
² Pathology Tissue Bank, Qilu Hospital of Shandong University , Jinan, China.
³ Research Institute of Breast Cancer, Shandong University, Jinan, China.

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.

Keywords: EMT; TAK1; TGF-β; TNBC; USP1; WDR48.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Movement / physiology
Epithelial-Mesenchymal Transition / physiology*
Female
Humans
Intracellular Signaling Peptides and Proteins / biosynthesis*
Intracellular Signaling Peptides and Proteins / genetics
MAP Kinase Kinase Kinases / biosynthesis*
MAP Kinase Kinase Kinases / genetics
Protein Stability
Transforming Growth Factor beta / biosynthesis*
Transforming Growth Factor beta / genetics
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism*
Ubiquitin-Specific Proteases / biosynthesis*
Ubiquitin-Specific Proteases / genetics

Substances

Intracellular Signaling Peptides and Proteins
Transforming Growth Factor beta
WDR48 protein, human
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7
USP1 protein, human
Ubiquitin-Specific Proteases

Grants and funding

This work was supported by the National Natural Science Foundation of China [No. 81672613; No. 81874119; No. 82072912]; Taishan Scholar Foundation of Shandong Province [No. ts20190971].