Background 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. Methods We 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. Results We 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s12943-019-1004-4) contains supplementary material, which is available to authorized users.

N6‐methyladenosine (m6A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated m6A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6A modification in the resistance of HCC to sorafenib therapy.

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N6-Methyladenosine (m6A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6A modification methyltransferase, demethylase and proteins that preferentially recognize m6A modification as “writers”, “erasers” and “readers”, respectively. Altered expression levels of the m6A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6A modification regulators for cancer drug development.