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NSUN2 介导的 RNA 5-甲基胞嘧啶通过 LIN28B 依赖的 GRB2 mRNA 稳定促进食管鳞状细胞癌进展。

NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization.

机构信息

State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.

出版信息

Oncogene. 2021 Sep;40(39):5814-5828. doi: 10.1038/s41388-021-01978-0. Epub 2021 Aug 3.

DOI:10.1038/s41388-021-01978-0
PMID:34345012
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8484015/
Abstract

5-Methylcytosine (mC) is a posttranscriptional RNA modification participating in many critical bioprocesses, but its functions in human cancer remain unclear. Here, by detecting the transcriptome-wide mC profiling in esophageal squamous cell carcinoma (ESCC), we showed increased mC methylation in ESCC tumors due to the overexpressed mC methyltransferase NSUN2. Aberrant expression of NSUN2 was positively regulated by E2F Transcription Factor 1 (E2F1). High NSUN2 levels predicted poor survival of ESCC patients. Moreover, silencing NSUN2 suppressed ESCC tumorigenesis and progression in Nsun2 knockout mouse models. Mechanistically, NSUN2 induced mC modification of growth factor receptor-bound protein 2 (GRB2) and stabilized its mRNA, which was mediated by a novel mC mediator, protein lin-28 homolog B (LIN28B). Elevated GRB2 levels increased the activation of PI3K/AKT and ERK/MAPK signalling. These results demonstrate that NSUN2 enhances the initiation and progression of ESCC via mC-LIN28B dependent stabilization of GRB2 transcript, providing a promising epitranscriptomic-targeted therapeutic strategy for ESCC.

摘要

5- 甲基胞嘧啶（mC）是一种参与许多关键生物过程的转录后 RNA 修饰物，但它在人类癌症中的功能尚不清楚。在这里，我们通过检测食管鳞状细胞癌（ESCC）中的全转录组 mC 谱，发现由于 mC 甲基转移酶 NSUN2 的过表达，ESCC 肿瘤中的 mC 甲基化增加。NSUN2 的异常表达受 E2F 转录因子 1（E2F1）的正调控。NSUN2 水平高预示着 ESCC 患者的生存不良。此外，沉默 NSUN2 抑制了 Nsun2 敲除小鼠模型中的 ESCC 肿瘤发生和进展。在机制上，NSUN2 通过一种新型 mC 介体蛋白 lin-28 同源物 B（LIN28B）诱导生长因子受体结合蛋白 2（GRB2）的 mC 修饰并稳定其 mRNA。升高的 GRB2 水平增加了 PI3K/AKT 和 ERK/MAPK 信号的激活。这些结果表明，NSUN2 通过 mC-LIN28B 依赖的 GRB2 转录物稳定增强 ESCC 的起始和进展，为 ESCC 提供了一种有前途的表观转录组靶向治疗策略。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6cf/8484015/45993d9b97aa/41388_2021_1978_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6cf/8484015/9a503d28db4f/41388_2021_1978_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6cf/8484015/2adcfe21760f/41388_2021_1978_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6cf/8484015/d5ab257a24e7/41388_2021_1978_Fig3_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c6cf/8484015/38cbd26f555b/41388_2021_1978_Fig5_HTML.jpg
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