RNA m6A 去甲基酶 FTO 通过表观遗传调控 LINC00022 的上调促进食管鳞状细胞癌的发生。
RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma.
机构信息
School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, China.
出版信息
J Exp Clin Cancer Res. 2021 Sep 20;40(1):294. doi: 10.1186/s13046-021-02096-1.
BACKGROUND
Long non-coding RNA (LncRNA) controls cell proliferation and plays a significant role in the initiation and progression of esophageal squamous cell carcinoma (ESCC). N6-methyladenosine (m6A) modification now is recognized as a master driver of RNA function to maintain homeostasis in cancer cells. However, how m6A regulates LncRNA function and its role in tumorigenesis of ESCC remain unclear.
METHODS
Multiple ESCC datasets were used to analyze gene expression in tumor tissues and normal tissues. Kaplan-Meier method and the ROC curve were conducted to evaluate the prognostic value and diagnostic value of LINC00022 in ESCC, respectively. Both gain-of-function and loss-of-function experiments were employed to investigate the effects of LINC00022 on ESCC growth in vitro and in vivo. Bioinformatics analysis, colorimetric m6A assay, RIP, MeRIP and co-IP was performed to explore the epigenetic mechanism of LINC00022 up-regulation in ESCC.
RESULTS
Here we report that m6A demethylation of LncRNA LINC00022 by fat mass and obesity-associated protein (FTO) promotes tumor growth of ESCC in vivo. Clinically, we revealed that LINC00022 was up-regulated in primary ESCC samples and was predictive of poor clinical outcome for ESCC patients. Mechanistically, LINC00022 directly binds to p21 protein and promotes its ubiquitination-mediated degradation, thereby facilitating cell-cycle progression and proliferation. Further, the elevated FTO in ESCC decreased m6A methylation of LINC00022 transcript, leading to the inhibition of LINC00022 decay via the m6A reader YTHDF2. Over-expression of FTO was shown to drive LINC00022-dependent cell proliferation and tumor growth of ESCC.
CONCLUSIONS
Thus, this study demonstrated m6A-mediated epigenetic modification of LncRNA contributes to the tumorigenesis in ESCC and LINC00022, specific target of m6A, serves as a potential biomarker for this malignancy.
背景
长链非编码 RNA（LncRNA）控制细胞增殖，在食管鳞状细胞癌（ESCC）的发生和发展中发挥重要作用。N6-甲基腺苷（m6A）修饰现在被认为是维持癌细胞内 RNA 功能平衡的主要驱动因素。然而，m6A 如何调节 LncRNA 的功能及其在 ESCC 肿瘤发生中的作用尚不清楚。
方法
使用多个 ESCC 数据集分析肿瘤组织和正常组织中的基因表达。Kaplan-Meier 法和 ROC 曲线分别用于评估 LINC00022 在 ESCC 中的预后价值和诊断价值。通过功能获得和功能丧失实验研究 LINC00022 对 ESCC 体外和体内生长的影响。进行生物信息学分析、比色 m6A 测定、RIP、MeRIP 和 co-IP 以探索 LINC00022 在 ESCC 中上调的表观遗传机制。
结果
我们报告说，肥胖相关蛋白（FTO）通过 m6A 去甲基化 LncRNA LINC00022 促进 ESCC 的体内肿瘤生长。临床上，我们发现 LINC00022 在原发性 ESCC 样本中上调，并可预测 ESCC 患者的不良临床结局。机制上，LINC00022 直接与 p21 蛋白结合并促进其泛素化介导的降解，从而促进细胞周期进程和增殖。此外，ESCC 中的升高的 FTO 降低了 LINC00022 转录本的 m6A 甲基化，导致 m6A 阅读器 YTHDF2 抑制 LINC00022 的降解。FTO 的过表达显示可驱动 LINC00022 依赖性 ESCC 细胞增殖和肿瘤生长。
结论
因此，本研究表明 LncRNA 的 m6A 介导的表观遗传修饰有助于 ESCC 的肿瘤发生，LINC00022 是 m6A 的特定靶标，可作为这种恶性肿瘤的潜在生物标志物。
Zotero 插件