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mA-甲基化的NUTM2B-AS1通过表观遗传激活转录促进肝癌干细胞特性

mA-Methylated NUTM2B-AS1 Promotes Hepatocellular Carcinoma Stemness Feature via Epigenetically Activating Transcription.

作者信息

Li Wenchuan, Zeng Min, Ning Yuanjia, Lu Rongzhou, Wei Yunyu, Xu Zuoming, Wei Huamei, Pu Jian

机构信息

Guangxi Clinical Medical Research Center for Hepatobiliary Diseases, Baise, People's Republic of China.

Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, People's Republic of China.

出版信息

J Hepatocell Carcinoma. 2024 Dec 3;11:2393-2411. doi: 10.2147/JHC.S480522. eCollection 2024.

DOI:10.2147/JHC.S480522
PMID:39649245
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11624692/
Abstract

PURPOSE

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Oncofetal proteins are the optimal diagnostic biomarkers and therapeutic targets for HCC. As the most abundant modification in RNA, N-methyladenosine (mA) has been reported to be involved in HCC initiation and progression. However, whether mA has oncofetal characteristics remains unknown.

METHODS

Gene expression in HCC tissues and cells was detected using qPCR. The level of mA methylation was determined using methylated RNA immunoprecipitation assay. The biological roles of NUTM2B-AS1 in HCC were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, and spheroid formation assays. The mechanisms underlying the roles of NUTM2B-AS1 were explored using RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), and assay for transposase-accessible chromatin (ATAC).

RESULTS

NUTM2B-AS1 was identified as a novel oncofetal long noncoding RNA that was upregulated in the fetal liver and HCC and silenced in adult liver tissues. METTL3 and METTL16 induce mA hypermethylation of NUTM2B-AS1. The mA methylation levels of NUTM2B-AS1 exhibit oncofetal characteristics. mA methylation upregulates NUTM2B-AS1 expression by increasing NUTM2B-AS1 transcript stability. mA-methylated NUTM2B-AS1 promotes HCC cell proliferation and stemness via epigenetically activating expression. NUTM2B-AS1 specifically binds to promoter. mA-methylated NUTM2B-AS1 is recognized by the mA reader YTHDC2, which further binds to the H3K4 methyltransferase MLL1. mA-methylated NUTM2B-AS1 recruits YTHDC2 and MLL1 to promoter, leading to increased H3K4me3 and chromatin accessibility at promoter. Functional rescue assays suggest that BMPR1A is a critical mediator of the oncogenic role of mA-methylated NUTM2B-AS1 in HCC.

CONCLUSION

METTL3- and METTL16-mediated mA methylation of NUTM2B-AS1 is a novel oncofetal molecular event in HCC that promotes HCC stemness via epigenetically activating transcription.

摘要

目的

肝细胞癌（HCC）是全球最致命的恶性肿瘤之一。癌胚蛋白是HCC的最佳诊断生物标志物和治疗靶点。作为RNA中最丰富的修饰，N-甲基腺苷（mA）已被报道参与HCC的发生和发展。然而，mA是否具有癌胚特征仍不清楚。

方法

使用qPCR检测HCC组织和细胞中的基因表达。使用甲基化RNA免疫沉淀法测定mA甲基化水平。使用细胞计数试剂盒-8、5-乙炔基-2'-脱氧尿苷掺入法和球体形成试验检测NUTM2B-AS1在HCC中的生物学作用。使用RNA免疫沉淀（RIP）、RNA纯化染色质分离（ChIRP）、染色质免疫沉淀（ChIP）和转座酶可及染色质分析（ATAC）探索NUTM2B-AS1作用的潜在机制。

结果

NUTM2B-AS1被鉴定为一种新型的癌胚长链非编码RNA，在胎儿肝脏和HCC中上调，在成人肝脏组织中沉默。METTL3和METTL16诱导NUTM2B-AS1的mA高甲基化。NUTM2B-AS1的mA甲基化水平表现出癌胚特征。mA甲基化通过增加NUTM2B-AS1转录本稳定性上调NUTM2B-AS1表达。mA甲基化的NUTM2B-AS1通过表观遗传激活 表达促进HCC细胞增殖和干性。NUTM2B-AS1特异性结合 启动子。mA甲基化的NUTM2B-AS1被mA阅读器YTHDC2识别，YTHDC2进一步与H3K4甲基转移酶MLL1结合。mA甲基化的NUTM2B-AS1将YTHDC2和MLL1募集到 启动子，导致 启动子处H3K4me3增加和染色质可及性增加。功能挽救试验表明，BMPR1A是mA甲基化的NUTM2B-AS1在HCC中致癌作用的关键介质。

结论

METTL3和METTL16介导的NUTM2B-AS1的mA甲基化是HCC中一种新型的癌胚分子事件，通过表观遗传激活 转录促进HCC干性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/61357b071a55/JHC-11-2393-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/8601c7b423ba/JHC-11-2393-g0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/823495c4391d/JHC-11-2393-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/788937031568/JHC-11-2393-g0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/61357b071a55/JHC-11-2393-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/8601c7b423ba/JHC-11-2393-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/195469ed66e8/JHC-11-2393-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/46f10d5922bb/JHC-11-2393-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/481318655cb7/JHC-11-2393-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/1cd5dfeb445d/JHC-11-2393-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/823495c4391d/JHC-11-2393-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/788937031568/JHC-11-2393-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/208322d61b3d/JHC-11-2393-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4097/11624692/61357b071a55/JHC-11-2393-g0009.jpg

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