RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3

Yi Niu,Heng Liang,Yuan Wang,Xiaobin Wu,Bo Wei,Lei Sun,Guohui Wan,Xi Li,Honglei Chen,Ziyou Lin,Xiao-Feng Xiong,Arabella Wan

doi:10.1186/s12943-019-1004-4

Abstract

BackgroundN6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood.MethodsWe used the m6A-RNA immunoprecipitation sequencing to identify the potential targets in breast cancer. To determine the underlying mechanism for the axis of FTO-BNIP3, we performed a series of in vitro and in vivo assays in 3 breast cancer cell lines and 36 primary breast tumor tissues and 12 adjunct tissues.ResultsWe showed that FTO, a key m6A demethylase, was up-regulated in human breast cancer. High level of FTO was significantly associated with lower survival rates in patients with breast cancer. FTO promoted breast cancer cell proliferation, colony formation and metastasis in vitro and in vivo. We identified BNIP3, a pro-apoptosis gene, as a downstream target of FTO-mediated m6A modification. Epigenetically, FTO mediated m6A demethylation in the 3’UTR of BNIP3 mRNA and induced its degradation via an YTHDF2 independent mechanism. BNIP3 acts as a tumor suppressor and is negatively correlated with FTO expression in clinical breast cancer patients. BNIP3 dramatically alleviated FTO-dependent tumor growth retardation and metastasis.ConclusionsOur findings demonstrate the functional significance of the m6A modification in breast cancer, and suggest that FTO may serve as a novel potential therapeutic target for breast cancer.

Highlights

N6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation
The m6A modification is mainly mediated by the methyltransferase (METTL3, Methyltransferase-like 14 (METTL14) and Wilms tumor associated protein (WTAP)) [8,9,10], demethylase (FTO and AlkB homolog 5 (ALKBH5)) [5, 11] and proteins that preferentially recognized m6A methylated transcripts (YTH domain family proteins [12,13,14,15,16], HNRNPA2B1 [17] and Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP) [18])
Fat mass and obesity-associated (FTO), an N6-methyladenosine RNA demethylase is upregulated in human breast cancer To investigate the role of m6A modification in breast cancers, we systematically analyzed the transcriptomic profiles of 111 breast tumors and 12 non-tumorous (NT) breast tissues (GSE9014, Additional file 2: Figure S1A), and identified that FTO, the core m6A demethylase, was significantly up-regulated in breast tumors compared with normal tissue (Fig. 1a and b)

Summary

Introduction

N6-methyladenosine (m6A) modification is the most pervasive modification in mRNA, and has been considered as a new layer of epigenetic regulation on mRNA processing, stability and translation. Despite its functional significance in various physiological processes, the role of the m6A modification involved in breast cancer is yet fully understood. It is estimated that more than 2.1 million new cases of breast cancer occurred in 2018, causing 627,000 death in women [1]. N6-methyladenosine (m6A) modification is the methylation of the adenosine base at the nitrogen-6 position of mRNA. Unlike other modifications of mRNA, the m6A modification is dynamically reversible as the DNA and histone modifications [5], and plays an critical role in regulating precursor mRNA maturation, translation and degradation [3, 6, 7]. Emergent evidence has shown that the m6A modification plays an important role in the occurrence and development of various human diseases [21,22,23,24]

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Results

Conclusion