对细胞周期蛋白D1的需求是肾癌细胞自主hif2依赖性的基础。

IF 29.7 1区 医学 Q1 ONCOLOGY
Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin
{"title":"对细胞周期蛋白D1的需求是肾癌细胞自主hif2依赖性的基础。","authors":"Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin","doi":"10.1158/2159-8290.CD-24-1378","DOIUrl":null,"url":null,"abstract":"<p><p>Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2a, bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent ccRCC lines treated with a belzutifan analog to identify HIF2a-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2a target gene CCND1, encoding Cyclin D1, promoted HIF2a-independence/belzutifan resistance. This activity requires Cdk4/6 activation by Cyclin D1, but is not solely due to phosphorylation of the canonical Cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2a-dependent. In this context, however, a kinase-defective Cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by Cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent Cyclin D1 activities.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7000,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Requirement for Cyclin D1 Underlies Cell Autonomous HIF2-Dependence in Kidney Cancer.\",\"authors\":\"Nitin H Shirole, Devishi Kesar, Yenarae Lee, Amy Goodale, Sudeepa Syamala, Shweta Kukreja, Rong Li, Xintao Qiu, Wenyu Yu, Seth Goldman, Paloma Cejas, Henry W Long, Karen Adelman, John G Doench, William R Sellers, William G Kaelin\",\"doi\":\"10.1158/2159-8290.CD-24-1378\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2a, bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent ccRCC lines treated with a belzutifan analog to identify HIF2a-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2a target gene CCND1, encoding Cyclin D1, promoted HIF2a-independence/belzutifan resistance. This activity requires Cdk4/6 activation by Cyclin D1, but is not solely due to phosphorylation of the canonical Cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2a-dependent. In this context, however, a kinase-defective Cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by Cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent Cyclin D1 activities.</p>\",\"PeriodicalId\":9430,\"journal\":{\"name\":\"Cancer discovery\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":29.7000,\"publicationDate\":\"2025-04-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/2159-8290.CD-24-1378\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-24-1378","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

VHL基因失活稳定HIF2a, HIF2a驱动透明细胞肾癌(ccRCC)。HIF2a抑制剂belzutifan被批准用于ccRCC治疗,但新发和获得性耐药很常见。与ARNT结合的HIF2a通过转录激活许多基因。我们在使用贝祖替芬类似物处理的hif2a依赖性ccRCC细胞系中进行了CRISPRa筛选,以鉴定在不下调时赋予细胞自主贝祖替芬抗性的hif2a应答基因。维持HIF2a靶基因CCND1的表达,编码Cyclin D1,促进HIF2a非依赖性/贝祖替芬耐药。这种活性需要Cdk4/6被Cyclin D1激活,但并不仅仅是由于典型的Cyclin D1靶点pRB的磷酸化。事实上,缺乏所有三个pRB家族成员的ccRCC系至少部分依赖于hif2a。然而,在这种情况下,激酶缺陷的Cyclin D1变体部分覆盖了belzutifan的抗增殖作用,这表明Cyclin D1促进ccRCC需要磷酸化pRB类似物和一种或多种激酶无关的Cyclin D1活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Requirement for Cyclin D1 Underlies Cell Autonomous HIF2-Dependence in Kidney Cancer.

Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2a, bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent ccRCC lines treated with a belzutifan analog to identify HIF2a-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2a target gene CCND1, encoding Cyclin D1, promoted HIF2a-independence/belzutifan resistance. This activity requires Cdk4/6 activation by Cyclin D1, but is not solely due to phosphorylation of the canonical Cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2a-dependent. In this context, however, a kinase-defective Cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by Cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent Cyclin D1 activities.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
×
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