Pharmacologic Induction of ERα SUMOylation Disrupts Its Chromatin Binding.

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Biology Pub Date : 2024-11-15 Epub Date: 2024-10-21 DOI:10.1021/acschembio.4c00606
Lizhen Wang, Ting Han
{"title":"Pharmacologic Induction of ERα SUMOylation Disrupts Its Chromatin Binding.","authors":"Lizhen Wang, Ting Han","doi":"10.1021/acschembio.4c00606","DOIUrl":null,"url":null,"abstract":"<p><p>Estrogen receptor α (ERα)-positive breast cancer patients are typically treated with ERα inhibitors, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, the distinct pharmacological properties of various ERα inhibitors remain incompletely understood. In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays confirmed that fulvestrant induces SUMOylation of ERα, which inhibits ERα's binding to chromatin DNA. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"2383-2392"},"PeriodicalIF":3.5000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574758/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1021/acschembio.4c00606","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/21 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Estrogen receptor α (ERα)-positive breast cancer patients are typically treated with ERα inhibitors, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, the distinct pharmacological properties of various ERα inhibitors remain incompletely understood. In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays confirmed that fulvestrant induces SUMOylation of ERα, which inhibits ERα's binding to chromatin DNA. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
药物诱导 ERα SUMOylation 会破坏其染色质结合。
雌激素受体α(ERα)阳性乳腺癌患者通常接受ERα抑制剂治疗,包括选择性雌激素受体调节剂(SERM)和选择性雌激素受体降解剂(SERD)。然而,人们对各种ERα抑制剂的不同药理特性仍不甚了解。在这项研究中,我们采用甲醛交联法,然后进行ERα免疫沉淀和质谱分析,揭示了氟维司群--第一种获得FDA批准的SERD--能诱导ERα与SUMO E3连接酶PIAS1和PIAS2之间的相互作用。生化和基因组测定证实,氟维司群可诱导ERα的SUMO化,从而抑制ERα与染色质DNA的结合。此外,雷洛昔芬(一种SERM)和艾拉司群(第一种经FDA批准的口服SERD)也被确认为同样能诱导ERα SUMO化并抑制其染色质相互作用的化合物。我们的研究结果揭示了选择性ERα抑制剂通过SUMOylation破坏ERα功能的机制,为开发下一代ERα靶向疗法提供了启示。
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 去求助
来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
期刊最新文献
Fluorescent d-amino Acid-Based Approach Enabling Fast and Reliable Measure of Antibiotic Susceptibility in Bacterial Cells. Intracellular Photocatalytic Proximity Labeling (iPPL) for Dynamic Analysis of Chromatin-Binding Proteins Targeting Histone H3. Bioorthogonal Cyclopropenones for Investigating RNA Structure. Molecular Targeted Engagement of DPP9 in Rat Tissue Using CETSA, SP3 Processing, and Absolute Quantitation Mass Spectrometry. Interspecies Crosstalk via LuxI/LuxR-Type Quorum Sensing Pathways Contributes to Decreased Nematode Survival in Coinfections of Pseudomonas aeruginosa and Burkholderia multivorans.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1