ZNF8 Orchestrates with Smad3 to Promote Lung Metastasis by Recruiting SMYD3 in Breast Cancer

Author:

Geng Wenwen12,An Junhua12,Dong Ke12,Zhang Hailu34,Zhang Xiuyuan3,Liu Yuchen3,Xu Rong3,Liu Yifan3,Huang Xiaofen34,Song Haiyun5,Yan Wei6,Sun Aihua347,He Fuchu37,Wang Jian34,Gao Haidong12,Tian Chunyan347ORCID

Affiliation:

1. Department of Breast Surgery Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University Qingdao Shandong 266000 China

2. Laboratory of Oncology Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University Qingdao Shandong 266000 China

3. State Key Laboratory of Medical Proteomics Beijing Proteome Research Center National Center for Protein Sciences (Beijing) Beijing Institute of Lifeomics Beijing 102206 China

4. College of Life Sciences Hebei University Baoding Hebei 071002 China

5. Department of Pathology Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University Qingdao Shandong 266000 China

6. The First Medical Center of Chinese PLA General Hospital Beijing 100036 China

7. Research Unit of Proteomics Dirven Cancer Precision Medicine Chinese Academy of Medical Sciences Beijing 102206 China

Abstract

AbstractMost deaths in breast cancer patients are attributed to metastasis, and lung metastasis is associated with a particularly poor prognosis; therefore it is imperative to identify potential target for intervention. The transforming growth factor‐β (TGF‐β) pathway plays a vital role in breast cancer metastasis, in which Smad3 is the key mediator and performs specific functions by binding with different cofactors. However, Smad3 cofactors involved in lung metastasis have not yet been identified. This study first establishes the interactome of Smad3 in breast cancer cells and identifies ZNF8 as a novel Smad3 cofactor. Furthermore, the results reveal that ZNF8 is closely associated with breast cancer lung metastasis prognosis, and specifically facilitates TGF‐β pathway‐mediated breast cancer lung metastasis by participating in multiple processes. Mechanistically, ZNF8 binds with Smad3 to enhance the H3K4me3 modification and promote the expression of lung metastasis signature genes by recruiting SMYD3. SMYD3 inhibition by BCI121 effectively prevents ZNF8‐mediated lung metastasis. Overall, the study identifies a novel cofactor of TGF‐β/Smad3 that promotes lung metastasis in breast cancer and introduces potential therapeutic strategies for the early management of breast cancer lung metastasis.

Funder

Applied Basic Research Fund of Qingdao

National Natural Science Foundation of China

Key Technologies Research and Development Program

Publisher

Wiley

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