YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m <sup>6</sup>A-dependent manner

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Abstract

Background

The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m ⁶A) 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 ⁶A-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 ⁶A-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.

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Most cited references 45

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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m6A-dependent regulation of messenger RNA stability

Xiao Wang, Zhike Lu, Adrián Gómez-Brandón … (2013)

N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.

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N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.

Xiao Wang, Boxuan Simen Zhao, Ian A Roundtree … (2015)

N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A-modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Print and electronic): January 2022

Publication date (Print): January 2022

Volume: 10

Issue: 2

Electronic Location Identifier: 83

Affiliations

[1 ]deptDepartment of Breast Surgery , Fujian Medical University Union Hospital , Fuzhou, China;

[2 ]deptDepartment of General Surgery , Fujian Medical University Union Hospital , Fuzhou, China;

[3 ]deptBreast Cancer Institute , Fujian Medical University , Fuzhou, China;

[4 ]deptDepartment of Pathology , Fujian Medical University Union Hospital , Fuzhou, China

Author notes

Contributions: (I) Conception and design: Y Lin, F Fu, C Wang; (II) Administrative support: Y Lin, J Zhang; (III) Provision of study materials or patients: X Jin, Q Nie, W Zhang, H Chen; (IV) Collection and assembly of data: W Guo, L Chen, M Chen; (V) Data analysis and interpretation: H Xiao, Y Li, X Chen, M Jiang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

[#]

These authors contributed equally to this work.

Correspondence to: Jie Zhang, PhD; Fangmeng Fu, PhD; Chuan Wang, PhD. Department of Breast Surgery, Fujian Medical University Union Hospital, No. 29, Xin Quan Road, Gulou District, Fuzhou 350001, China. Email: zj1979@ 123456hotmail.com ; ffm@ 123456fjmu.edu.cn ; chuanwang1968@ 123456outlook.com .

[^]

ORCID: 0000-0002-3963-3468.

Article

Publisher ID: atm-10-02-83

DOI: 10.21037/atm-21-6857

PMC ID: 8848410

PubMed ID: 35282088

SO-VID: 6e15c12f-8688-4abb-a2fe-6839a720261f

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

History

Date received : 30 November 2021

Date accepted : 14 January 2022

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