RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m(6)A-YTHDF2-dependent manner.
RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m(6)A-YTHDF2-dependent manner.
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RNA N6-甲基腺苷脱甲基酶 FTO 通过 m6A-YTHDF2 依赖性方式诱导 PDGFC 自分泌活性，促进胰腺癌进展
DOI：
10.1038/s41388-022-02306-w
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发表时间：
2022-05
期刊：
影响因子：
8
通讯作者：
Liang, Chen
中科院分区：
文献类型：
--
作者：
Tan, Zhen;Shi, Si;Xu, Jin;Liu, Xiaomeng;Lei, Yubin;Zhang, Bo;Hua, Jie;Meng, Qingcai;Wang, Wei;Yu, Xianjun;Liang, Chen
RNA N6-甲基腺苷（m6 A）是一种新兴的mRNA修饰调节剂，代表了肿瘤发生中的一个新角色。尽管m6 A修饰在病理和生理过程中具有重要的功能意义，但其在胰腺导管癌（PDAC）中的作用仍然是难以捉摸的。在这里，我们发现高脂肪量和肥胖相关基因（FTO）表达与PDAC患者的不良预后相关，并且FTO表达的抑制抑制了细胞增殖。在此，进行m6 A测序（m6 A-seq）以筛选FTO靶向的基因。在体外和体内研究了FTO刺激对胰腺癌细胞生物学特性的影响，包括增殖和集落形成。结果表明，FTO直接靶向血小板衍生生长因子C（PDGFC），并以m6 A-YTHDF 2依赖性方式稳定其mRNA表达。采用m6 A-甲基化RNA免疫沉淀-qPCR（MeRIP-qPCR）、RNA免疫沉淀（RIP）和荧光素酶报告基因测定来验证FTO与PDGFC的特异性结合。PDGFC上调导致Akt信号通路的重新激活，促进细胞生长。总体而言，我们的研究表明，FTO下调导致PDGFC的3个UTR中m6 A修饰增加，然后以m6 A-YTHDF 2依赖性方式调节其转录水平的降解，突出了PDAC治疗和预后预测的潜在治疗靶点。
RNA N6-methyladenosine (m6A) is an emerging regulator of mRNA modifications and represents a novel player in tumorigenesis. Although it has functional significance in both pathological and physiological processes, the role of m6A modification in pancreatic ductal cancer (PDAC) remains elusive. Here, we showed that high fat mass and obesity-associated gene (FTO) expression was associated with a poor prognosis in PDAC patients and that suppression of FTO expression inhibited cell proliferation. Here, m6A sequencing (m6A-seq) was performed to screen genes targeted by FTO. The effects of FTO stimulation on the biological characteristics of pancreatic cancer cells, including proliferation and colony formation, were investigated in vitro and in vivo. The results indicate that FTO directly targets platelet-derived growth factor C (PDGFC) and stabilizes its mRNA expression in an m6A-YTHDF2-dependent manner. m6A-methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to validate the specific binding of FTO to PDGFC. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting cell growth. Overall, our study reveals that FTO downregulation leads to increased m6A modifications in the 3ʹ UTR of PDGFC and then modulates the degradation of its transcriptional level in an m6A-YTHDF2-dependent manner, highlighting a potential therapeutic target for PDAC treatment and prognostic prediction.
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