YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner.
YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner.
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YTHDF1 通过以 m6A 依赖性方式促进 FOXM1 翻译来促进乳腺癌进展
DOI：
10.1186/s13578-022-00759-w
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发表时间：
2022-02-23
影响因子：
7.5
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Chen H;Yu Y;Yang M;Huang H;Ma S;Hu J;Xi Z;Guo H;Yao G;Yang L;Huang X;Zhang F;Tan G;Wu H;Zheng W;Li L
背景N6-甲基腺苷（m6 A）是RNA水平上最常见的转录后修饰。然而，乳腺癌中的m6 A表观遗传调控的确切分子机制在很大程度上仍然是未知的，需要充分elaborated.MethodsThe整合的生物信息学分析被用来筛选临床相关性和失调的m6 A“阅读器”蛋白YTHDF 1在乳腺癌从TCGA数据库，这是进一步验证了在一个队列的临床标本。通过CCK-8、EdU、创伤愈合、transwell侵袭和细胞周期等功能实验，研究YTHDF 1在乳腺癌中的生物学作用。用RIP、m6 A-IP和CLIP方法检测YTHDF 1的靶基因，并通过RT-qPCR、western blot、polysome profiling等方法进行验证。YTHDF 1和FOXM 1之间的蛋白质-蛋白质相互作用通过免疫共沉淀检测。ResultsYTHDF 1在乳腺癌细胞和临床组织标本中过表达。YTHDF 1的高表达水平与乳腺癌患者肿瘤大小、淋巴结浸润和远处转移呈正相关。YTHDF 1基因缺失可抑制乳腺癌细胞的增殖、侵袭和上皮间质转化（EMT），并诱导乳腺癌细胞阻滞于G 0/G1期。我们还证明了FOXM 1是YTHDF 1的靶点。YTHDF 1通过识别并结合m6 A修饰的FOXM 1 mRNA，加速FOXM 1的翻译过程，促进乳腺癌的转移。而FOXM 1在乳腺癌细胞中的过表达部分抵消了YTHDF 1沉默所产生的抑瘤效应，进一步证实了YTHDF 1与FOXM 1之间的调控关系。结论YTHDF 1/FOXM 1调控通路参与了乳腺癌的转移和进展，提示YTHDF 1有可能成为潜在的生物标志物和治疗靶点。这也促进了我们对m6 A表观遗传调控乳腺癌肿瘤发生的理解。
BackgroundN6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated.MethodsThe integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A “reader” protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein–protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation.ResultsOur study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1.ConclusionOur study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.
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