Hypoxia inducible factor-1α drives cancer resistance to cuproptosis

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-03-06 DOI:10.1016/j.ccell.2025.02.015

Zhou Yang, Wei Su, Xiyi Wei, Yitong Pan, Mengying Xing, Lili Niu, Baijie Feng, Weiyu Kong, Xiaohan Ren, Feng Huang, Jingwan Zhou, Wei Zhao, Yingyi Qiu, Tian Liao, Qi Chen, Shuang Qu, Yunjun Wang, Qing Guan, Duanshu Li, Ke Zen, Bing Yao

{"title":"Hypoxia inducible factor-1α drives cancer resistance to cuproptosis","authors":"Zhou Yang, Wei Su, Xiyi Wei, Yitong Pan, Mengying Xing, Lili Niu, Baijie Feng, Weiyu Kong, Xiaohan Ren, Feng Huang, Jingwan Zhou, Wei Zhao, Yingyi Qiu, Tian Liao, Qi Chen, Shuang Qu, Yunjun Wang, Qing Guan, Duanshu Li, Ke Zen, Bing Yao","doi":"10.1016/j.ccell.2025.02.015","DOIUrl":null,"url":null,"abstract":"Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis <em>in vivo</em>. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"17 1","pages":""},"PeriodicalIF":48.8000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2025.02.015","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Cuproptosis represents a new type of cell death that intricately associated with copper homeostasis and protein lipoylation. The cuproptosis suppression has been characterized in the hypoxic tumor microenvironment (TME). Here we reveal that hypoxia inducible factor-1α (HIF-1α) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1α activates pyruvate dehydrogenase kinase 1 and 3 (PDK1/3), resulting in decreased expression of dihydrolipoamide S-acetyltransferase (DLAT) (target of copper), and promotes the accumulation of metallothionein, which sequesters mitochondrial copper, leading to resistance to cuproptosis under hypoxic conditions. Furthermore, we discovered that high levels of copper reduce ubiquitination and increase the stability of HIF-1α protein without affecting its mRNA levels. Inhibition of HIF-1α increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1α in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.