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

Yuxiang Lin; Xuan Jin; Qian Nie; Minyan Chen; Wenhui Guo; Lili Chen; Yan Li; Xiaobin Chen; Wenzhe Zhang; Hanxi Chen; Meichen Jiang; Han Xiao; Jie Zhang; Fangmeng Fu; Chuan Wang

doi:10.21037/atm-21-6857

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

Ann Transl Med. 2022 Jan;10(2):83. doi: 10.21037/atm-21-6857.

Authors

Yuxiang Lin^#^{1

2

3}, Xuan Jin^#^{1

2

3}, Qian Nie^#^{1

2

3}, Minyan Chen^#^{1

2

3}, Wenhui Guo^{1

2

3}, Lili Chen^{1

2

3}, Yan Li^{1

2

3}, Xiaobin Chen^{1

2

3}, Wenzhe Zhang^{1

2

3}, Hanxi Chen^{1

2

3}, Meichen Jiang⁴, Han Xiao⁴, Jie Zhang^{1

2

3}, Fangmeng Fu^{1

2

3}, Chuan Wang^{1

2

3}

Affiliations

¹ Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
² Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
³ Breast Cancer Institute, Fujian Medical University, Fuzhou, China.
⁴ Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, China.

^# Contributed equally.

Abstract

Background: The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m⁶A) 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 m⁶A-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 m⁶A-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.

Keywords: Triple-negative breast cancer (TNBC); YTH domain family 3 (YTHDF3); epithelial-mesenchymal transition (EMT); metastasis; zinc finger E-box-binding homeobox 1 (ZEB1).