K542 acetylation promotes YTHDF2 binding to m6A-modified mRNAs and fosters colorectal cancer progression

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research Pub Date : 2025-07-05 DOI:10.1016/j.yexcr.2025.114667

Bo Wen , Shiwei Feng , Lin Bao , Sheng Li , Yanping Yang , Shiyou Long , Jian Xiao , Shujuan Li , Yujie Hou , Sisi Liu

{"title":"K542 acetylation promotes YTHDF2 binding to m6A-modified mRNAs and fosters colorectal cancer progression","authors":"Bo Wen , Shiwei Feng , Lin Bao , Sheng Li , Yanping Yang , Shiyou Long , Jian Xiao , Shujuan Li , Yujie Hou , Sisi Liu","doi":"10.1016/j.yexcr.2025.114667","DOIUrl":null,"url":null,"abstract":"<div><div>N6-methyladenosine (m6A) modification serves as a crucial regulator of diverse biological processes and disease progression. A central player in m6A regulation is YT521-B homology domain family member 2 (YTHDF2), a well-characterized m6A-binding protein primarily involved in mRNA stabilization. This study identifies lysine 542 (K542) as a critical acetylation site on YTHDF2, regulated by p300 as the acetyltransferase and SIRT2 as the deacetylase. Notably, while K542 acetylation has minimal effects on YTHDF2's protein stability or subcellular localization, it significantly enhances the protein's binding affinity for m6A-modified mRNAs. This enhanced binding affinity has profound biological implications, as K542 acetylation promotes malignant phenotypes in colorectal cancer (CRC) cells in vitro and <em>in vivo</em>. Supporting its clinical relevance, analysis of CRC tissues reveals elevated levels of YTHDF2 acetylation in primary tumors, strongly associating this modification with CRC pathology. Collectively, these findings highlight K542 acetylation as a key enhancer of YTHDF2's m6A recognition and a critical driver of its oncogenic activity.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"450 2","pages":"Article 114667"},"PeriodicalIF":3.5000,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014482725002678","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

N6-methyladenosine (m6A) modification serves as a crucial regulator of diverse biological processes and disease progression. A central player in m6A regulation is YT521-B homology domain family member 2 (YTHDF2), a well-characterized m6A-binding protein primarily involved in mRNA stabilization. This study identifies lysine 542 (K542) as a critical acetylation site on YTHDF2, regulated by p300 as the acetyltransferase and SIRT2 as the deacetylase. Notably, while K542 acetylation has minimal effects on YTHDF2's protein stability or subcellular localization, it significantly enhances the protein's binding affinity for m6A-modified mRNAs. This enhanced binding affinity has profound biological implications, as K542 acetylation promotes malignant phenotypes in colorectal cancer (CRC) cells in vitro and in vivo. Supporting its clinical relevance, analysis of CRC tissues reveals elevated levels of YTHDF2 acetylation in primary tumors, strongly associating this modification with CRC pathology. Collectively, these findings highlight K542 acetylation as a key enhancer of YTHDF2's m6A recognition and a critical driver of its oncogenic activity.

查看原文本刊更多论文

K542乙酰化促进YTHDF2与m6a修饰的mrna结合并促进结直肠癌的进展

n6 -甲基腺苷（m6A）修饰是多种生物过程和疾病进展的重要调节因子。m6A调控的核心参与者是YT521-B同源结构域家族成员2 (YTHDF2)，这是一种特性良好的m6A结合蛋白，主要参与mRNA稳定。本研究发现赖氨酸542 （K542）是YTHDF2上的一个关键乙酰化位点，由p300作为乙酰转移酶和SIRT2作为去乙酰化酶调节。值得注意的是，虽然K542乙酰化对YTHDF2蛋白稳定性或亚细胞定位的影响很小，但它显著增强了蛋白对m6a修饰mrna的结合亲和力。这种增强的结合亲和力具有深远的生物学意义，因为K542乙酰化在体外和体内促进结直肠癌（CRC）细胞的恶性表型。支持其临床相关性，对结直肠癌组织的分析显示原发性肿瘤中YTHDF2乙酰化水平升高，这种修饰与结直肠癌病理密切相关。总的来说，这些发现强调了K542乙酰化是YTHDF2识别m6A的关键增强子，也是其致癌活性的关键驱动因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Experimental cell research 医学-细胞生物学

CiteScore

7.20

自引率

0.00%

发文量

295

审稿时长

30 days

期刊介绍： Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.