Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer
Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer
复制标题
METTL14上调介导PERP mRNA N6腺苷甲基化升高促进胰腺癌生长和转移
DOI：
10.1186/s12943-020-01249-8
复制
发表时间：
2020-08-25
期刊：
影响因子：
37.3
通讯作者：
Qin, Renyi
中科院分区：
文献类型：
--
作者：
Wang, Min;Liu, Jun;Qin, Renyi
背景胰腺癌是人类致死率最高的恶性肿瘤之一，N6-甲基腺苷（m6 A）是真核生物中常见的一种mRNA修饰，在胰腺癌的生理和病理过程中起着重要作用。然而，它在胰腺癌中的作用仍然habitued.MethodsLC/MS被用来配置文件m6 A在胰腺癌和正常组织中的水平。生物信息学分析，实时PCR，免疫组织化学和蛋白质印迹法被用来确定在胰腺癌中的作用m6 A调节剂。利用体外和体内模型研究了甲基转移酶样14（胃L14）的生物学效应，胃L14是mRNA甲基化酶。MeRIP-Seq和RNA-Seq用于评估胃L14的下游靶点。结果我们发现在大约70%的胰腺癌样品中m6 A水平升高。此外，我们证明了胃L14是调节m6 A甲基化（甲基化的频率和位点）的主要酶。在体外和体内，通过以m6 A依赖性方式直接靶向下游PERPmRNA（与PMP-22相关的p53效应子），过表达胃L14显著促进胰腺癌细胞增殖和迁移。靶腺苷甲基化导致PERPmRNA周转增加，从而降低胰腺癌细胞中PERP（mRNA和蛋白）的水平.ConclusionsOur数据表明，胃L14的上调通过m6 A修饰导致PERP水平降低，促进胰腺癌的生长和转移;因此胃L14是其治疗的潜在治疗靶点。
BackgroundPancreatic cancer is one of the most lethal human cancers.N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive.MethodsLC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.ResultsWe found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo,via direct targeting of the downstreamPERPmRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increasedPERPmRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.ConclusionsOur data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.