RNA N6-methyladenosine demethylase FTO promotes breast tumor progression updates through inhibiting BNIP3
RNA N6-methyladenosine demethylase FTO promotes breast tumor progression updates through inhibiting BNIP3
复制标题
RNA N6-甲基腺苷脱甲基酶 FTO 通过抑制 BNIP3 促进乳腺肿瘤进展
DOI：
10.1186/s12943-019-1004-4
复制
发表时间：
2019-03-28
期刊：
影响因子：
37.3
通讯作者：
Wan, Guohui
中科院分区：
文献类型：
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作者：
Niu, Yi;Lin, Ziyou;Wan, Guohui
背景N6-甲基腺苷（m6A）修饰是mRNA中最普遍的修饰，并被认为是mRNA加工、稳定性和翻译的新表观遗传调控层。尽管m6A修饰在多种生理过程中具有重要的功能，但其在乳腺癌中的作用尚未完全了解。方法我们使用m6A-RNA免疫沉淀测序来鉴定乳腺癌中的潜在靶点。为了确定 FTO-BNIP3 轴的潜在机制，我们在 3 种乳腺癌细胞系、36 个原发性乳腺肿瘤组织和 12 个附属组织中进行了一系列体外和体内测定。结果我们表明，FTO（一种关键的 m6A 去甲基化酶）在人类乳腺癌中上调。高水平的 FTO 与乳腺癌患者较低的生存率显着相关。 FTO在体外和体内促进乳腺癌细胞增殖、集落形成和转移。我们确定了 BNIP3（一种促凋亡基因）作为 FTO 介导的 m6A 修饰的下游靶标。从表观遗传学角度来看，FTO 介导 BNIP3 mRNA 3’UTR 中的 m6A 去甲基化，并通过 YTHDF2 独立机制诱导其降解。 BNIP3 作为肿瘤抑制因子，与临床乳腺癌患者中 FTO 的表达呈负相关。 BNIP3 显着缓解 FTO 依赖性肿瘤生长迟缓和转移。结论我们的研究结果证明了 m6A 修饰在乳腺癌中的功能意义，并表明 FTO 可能作为乳腺癌的新的潜在治疗靶点。
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.