The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Pratikshya Shrestha, Garam Kim, Hyelim Kang, Poshan Yugal Bhattarai, Hong Seok Choi
{"title":"The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA","authors":"Pratikshya Shrestha,&nbsp;Garam Kim,&nbsp;Hyelim Kang,&nbsp;Poshan Yugal Bhattarai,&nbsp;Hong Seok Choi","doi":"10.1007/s12272-023-01480-z","DOIUrl":null,"url":null,"abstract":"<div><p>The post-transcriptional processing of <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpression increased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-tagged RNA pull-down assay, we identified Aurora kinase A (<i>AURKA</i>) mRNA as a bona fide substrate of YTHDF1. PIN1-mediated YTHDF1 stabilization increased the stability of <i>AURKA</i> mRNA in an m<sup>6</sup>A-dependent manner. Furthermore, YTHDF1 knockout reduced AURKA protein expression levels, resulting in anticancer effects in breast cancer cells, including decreased cell proliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancer effects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 produced comparable anticancer effects to those observed in YTHDF1-knockout cells, and these effects were reversed upon overexpression of YTHDF1. In conclusion, the findings of our study suggest that increased YTHDF1 stability induced by PIN1 promotes breast tumorigenesis via the stabilization of <i>AURKA</i> mRNA. Targeting the PIN1/YTHDF1 axis may represent a novel therapeutic strategy for breast cancer.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":null,"pages":null},"PeriodicalIF":6.9000,"publicationDate":"2023-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Pharmacal Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s12272-023-01480-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

Abstract

The post-transcriptional processing of N6-methyladenosine (m6A)-modified mRNA by YTH domain-containing family protein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequently upregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. The WW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpression increased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-tagged RNA pull-down assay, we identified Aurora kinase A (AURKA) mRNA as a bona fide substrate of YTHDF1. PIN1-mediated YTHDF1 stabilization increased the stability of AURKA mRNA in an m6A-dependent manner. Furthermore, YTHDF1 knockout reduced AURKA protein expression levels, resulting in anticancer effects in breast cancer cells, including decreased cell proliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancer effects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 produced comparable anticancer effects to those observed in YTHDF1-knockout cells, and these effects were reversed upon overexpression of YTHDF1. In conclusion, the findings of our study suggest that increased YTHDF1 stability induced by PIN1 promotes breast tumorigenesis via the stabilization of AURKA mRNA. Targeting the PIN1/YTHDF1 axis may represent a novel therapeutic strategy for breast cancer.

Abstract Image

Abstract Image

PIN1-YTHDF1 轴通过 m6A 依赖性稳定 AURKA mRNA 促进乳腺肿瘤发生。
含YTH结构域的家族蛋白1(YTHDF1)对N6-甲基腺苷(m6A)修饰的mRNA进行转录后处理在基因表达调控中起着至关重要的作用。虽然 YTHDF1 的表达在乳腺癌中经常上调,但其调控机制仍不清楚。在这项研究中,我们研究了肽基-脯氨酰-顺反异构酶 NIMA-interacting 1(PIN1)在乳腺癌细胞中调控 YTHDF1 稳定性的作用。PIN1的WW结构域以磷酸化依赖的方式与YTHDF1相互作用。此外,PIN1的过表达可阻止泛素依赖性蛋白酶体降解,从而增加YTHDF1的稳定性。此外,利用MS2标记的RNA牵引试验,我们发现极光激酶A(AURKA)mRNA是YTHDF1的真正底物。PIN1 介导的 YTHDF1 稳定化以 m6A 依赖性方式增加了 AURKA mRNA 的稳定性。此外,YTHDF1基因敲除降低了AURKA蛋白的表达水平,从而对乳腺癌细胞产生抗癌作用,包括细胞增殖减少、细胞周期停滞在G0/G1期、细胞凋亡和球形体形成减少。AURKA 的过表达逆转了 YTHDF1 基因敲除诱导的抗癌效应。同样,PIN1基因敲除产生的抗癌效应与YTHDF1基因敲除细胞中观察到的抗癌效应相当,而过表达YTHDF1可逆转这些效应。总之,我们的研究结果表明,PIN1诱导的YTHDF1稳定性增加会通过稳定AURKA mRNA促进乳腺癌的发生。靶向 PIN1/YTHDF1 轴可能是治疗乳腺癌的一种新策略。
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
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信