YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m6A-dependent manner

被引：50

作者：

Lin, Yuxiang ^{[1
,2
,3
]}

Jin, Xuan ^{[1
,2
,3
]}

Nie, Qian ^{[1
,2
,3
]}

Chen, Minyan ^{[1
,2
,3
]}

Guo, Wenhui ^{[1
,2
,3
]}

Chen, Lili ^{[1
,2
,3
]}

Li, Yan ^{[1
,2
,3
]}

Chen, Xiaobin ^{[1
,2
,3
]}

Zhang, Wenzhe ^{[1
,2
,3
]}

Chen, Hanxi ^{[1
,2
,3
]}

Jiang, Meichen ^{[4
]}

Xiao, Han ^{[4
]}

Zhang, Jie ^{[1
,2
,3
]}

Fu, Fangmeng ^{[1
,2
,3
]}

Wang, Chuan ^{[1
,2
,3
]}

机构：

[1] Fujian Med Univ, Dept Breast Surg, Union Hosp, 29 Xin Quan Rd, Fuzhou 350001, Peoples R China

[2] Fujian Med Univ, Dept Gen Surg, Union Hosp, Fuzhou, Peoples R China

[3] Fujian Med Univ, Breast Canc Inst, Fuzhou, Peoples R China

[4] Fujian Med Univ, Dept Pathol, Union Hosp, Fuzhou, Peoples R China

来源：

ANNALS OF TRANSLATIONAL MEDICINE | 2022年 / 10卷 / 02期

关键词：

Triple-negative breast cancer (TNBC); metastasis; epithelial-mesenchymal transition (EMT); YTH domain family 3 (YTHDF3); zinc finger E-box-binding homeobox 1 (ZEB1); METHYLTRANSFERASE METTL3 PROMOTES; EMT-ACTIVATOR ZEB1; CELL PLASTICITY; TRANSLATION; STEMNESS;

D O I：

10.21037/atm-21-6857

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m(6)A) reader which is involved in multiple cancers. However, the biological role and mechanisms of action for YTHDF3 in triple-negative breast cancer (TNBC) remains to be elucidated. Methods: The expression of YTHDF3 in TNBC tissues was evaluated using The Cancer Genome Atlas (TCGA) database, BC-GenExMiner, and immunohistochemistry (IHC) staining. Cell migration, invasion, and epithelial-mesenchymal transition (EMT) were validated by wound healing assays, transwell assays, and Western blot (WB) analyses. The association between YTHDF3 and zinc finger E-box-binding homeobox 1 (ZEB1) was confirmed by Pearson correlation analysis. RNA-binding protein immunoprecipitation (RIP) assays and mRNA actinomycin stability analyses were applied to confirm whether YTHDF3 could interact with ZEB1in an m(6)A-dependent manner. Results: The expression of YTHDF3 was correlated with poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Functional experiments indicated that YTHDF3 positively regulated cell migration, invasion, and EMT in TNBC cells. Moreover, ZEB1 was identified as a key downstream target for YTHDF3 and YTHDF3 could enhance ZEB1 mRNA stability in an m(6)A-dependent manner. Inhibition of YTHDF3 reduced migration, invasion, and EMT, all of which were reversed by rescue experiments overexpressing ZEB1. Conclusions: The findings herein confirmed that the YTHDF3/ZEB1 axis plays an important role in the progression and metastasis of TNBC. YTHDF3 is a promising prognosis biomarker and potential therapeutic target for patients with TNBC.

引用

页数：15

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