The m(6)A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m(6)A-Dependent Manner.
The m(6)A Reader YTHDF1 Facilitates the Tumorigenesis and Metastasis of Gastric Cancer via USP14 Translation in an m(6)A-Dependent Manner.
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DOI：
10.3389/fcell.2021.647702
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhu JS
中科院分区：
文献类型：
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作者：
Chen XY;Liang R;Yi YC;Fan HN;Chen M;Zhang J;Zhu JS
N6-甲基腺苷（m6 A）RNA甲基化通过影响mRNA修饰参与多种癌症的进展。YTHDF 1在胃癌（GC）中可作为癌基因发挥作用，而YTHDF 1通过m6 A修饰调节胃肿瘤发生的生物学机制在很大程度上仍不清楚。分析了GEO和TCGA队列中GC临床标本中差异表达的m6 A修饰组分及其与临床预后的相关性。采用Transwell和流式细胞术检测YTHDF 1在胃癌中的表型，并建立胃癌皮下移植瘤模型和肺癌转移模型。使用RNA/MeRIP-seq的交叉、荧光素酶测定、RIP-PCR、RNA下拉和MeRIP-PCR来鉴定GC细胞中YTHDF 1修饰的USP 14及其m6 A水平。YTHDF 1在胃癌组织中高表达，与胃癌患者预后不良有关，是胃癌患者预后不良的独立预后因素。YTHDF 1缺陷抑制细胞增殖和侵袭（体外），胃肿瘤发生和肺转移（体内），也诱导细胞凋亡。交叉实验表明YTHDF 1以m6 A依赖的方式促进USP 14蛋白的翻译。USP 14的上调与YTHDF 1的表达呈正相关，提示胃癌预后不良。我们的数据表明，m6 A阅读器YTHDF 1通过促进USP 14蛋白翻译以m6 A依赖的方式促进GC的肿瘤发生和转移，并可能为GC治疗提供潜在的靶点。
N6-methyladenosine (m6A) RNA methylation is implicated in the progression of multiple cancers via influencing mRNA modification. YTHDF1 can act as an oncogene in gastric cancer (GC), while the biological mechanisms via which YTHDF1 regulates gastric tumorigenesis through m6A modification remain largely unknown. GEO and TCGA cohorts were analyzed for differentially expressed m6A modification components in GC clinical specimens and their association with clinical prognosis. Transwell and flow cytometry assays as well as subcutaneous xenograft and lung metastasis models were used to evaluate the phenotype of YTHDF1 in GC. Intersection of RNA/MeRIP-seq, luciferase assay, RIP-PCR, RNA pull-down and MeRIP-PCR was used to identify YTHDF1- modified USP14 and its m6A levels in GC cells. High-expressed YTHDF1 was found in GC tissues and was related to poor prognosis, acting as an independent prognostic factor of poor survival in GC patients. YTHDF1 deficiency inhibited cell proliferation and invasion (in vitro), and gastric tumorigenesis and lung metastasis (in vivo) and also induced cell apoptosis. Intersection assays revealed that YTHDF1 promoted USP14 protein translation in an m6A-dependent manner. USP14 upregulation was positively correlated with YTHDF1 expression and indicated a poor prognosis in GC. Our data suggested that m6A reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an m6A-dependent manner and might provide a potential target for GC treatment.
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