Hypoxia inducible factor-1a drives cancer resistance to cuproptosis

被引：11

作者：

Yang, Zhou ^{[1
,2
]}

Su, Wei ^{[1
,2
,3
]}

Wei, Xiyi ^{[4
]}

Pan, Yitong ^{[5
]}

Xing, Mengying ^{[6
]}

Niu, Lili ^{[7
]}

Feng, Baijie ^{[8
]}

Kong, Weiyu ^{[4
]}

Ren, Xiaohan ^{[4
]}

Huang, Feng ^{[9
]}

Zhou, Jingwan ^{[9
]}

Zhao, Wei ^{[10
,11
]}

Qiu, Yingyi ^{[9
]}

Liao, Tian ^{[1
,2
]}

Chen, Qi ^{[1
,2
]}

Qu, Shuang ^{[12
]}

Wang, Yunjun ^{[1
,2
]}

Guan, Qing ^{[1
,2
]}

Li, Duanshu ^{[1
,2
]}

Zen, Ke ^{[6
]}

Chen, Yun ^{[13
,14
]}

Qin, Chao ^{[4
]}

Wang, Yu ^{[1
,2
]}

Zhou, Xiang ^{[2
,15
,16
]}

Xiang, Jun ^{[1
,2
]}

Yao, Bing ^{[9
,17
,18
]}

机构：

[1] Fudan Univ, Shanghai Canc Ctr, Dept Head & Neck Surg, Shanghai, Peoples R China

[2] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China

[3] Fudan Univ, Shanghai Canc Ctr, Dept Med Oncol, Shanghai, Peoples R China

[4] Nanjing Med Univ, Affiliated Hosp 1, Dept Urol, Nanjing, Peoples R China

[5] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genom & Precis Med, Beijing, Peoples R China

[6] Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing, Peoples R China

[7] Tongji Univ, Med Sch, Shanghai Pulm Hosp, Canc Inst,Dept Integrat Med, Shanghai, Peoples R China

[8] Fudan Univ, Pudong Med Ctr, Shanghai Pudong Hosp, Dept Med Oncol, Shanghai 201399, Peoples R China

[9] Nanjing Med Univ, Natl Expt Teaching Ctr Basic Med Sci, Sch Basic Med Sci, Dept Med Genet, Nanjing, Peoples R China

[10] Chengdu Med Coll, Sch Lab Med, Dept Clin Biochem, Chengdu, Peoples R China

[11] Chengdu Med Coll, Affiliated Hosp 1, Sch Lab Med, Dept Clin Biochem, Chengdu, Peoples R China

[12] Nanjing Med Univ, Geriatr Hosp, Nanjing, Jiangsu, Peoples R China

[13] Nanjing Med Univ, Res Ctr Surg, Nanjing BenQ Med Ctr, Affiliated BenQ Hosp, Nanjing, Peoples R China

[14] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Sch Basic Med Sci,Dept Immunol, Nanjing 211, Jiangsu, Peoples R China

[15] Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China

[16] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China

[17] Nanjing Med Univ, Affiliated Taizhou Peoples Hosp, Taizhou Sch Clin Med, Dept Gen Surg, Taizhou 225300, Jiangsu, Peoples R China

[18] Nanjing Med Univ, Jiangsu Prov Engn Res Ctr Antibody Drug, State Key Lab Cultivat Base Biomarkers Canc Precis, NHC Key Lab Antibody Tech, Nanjing, Peoples R China

来源：

CANCER CELL | 2025年 / 43卷 / 05期

基金：

中国国家自然科学基金;

关键词：

PYRUVATE-DEHYDROGENASE KINASE; DIHYDROLIPOYL ACETYLTRANSFERASE; COPPER HOMEOSTASIS; SIGNALING AXIS; CELL-DEATH; PHOSPHORYLATION; EXPRESSION; BINDING; CERULOPLASMIN; METABOLISM;

D O I：

10.1016/j.ccell.2025.02.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-1a (HIF-1a) is a driver of cuproptosis resistance in solid tumor. We found that HIF-1a 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-1a protein without affecting its mRNA levels. Inhibition of HIF-1a increases the susceptibility of cancer to cuproptosis in vivo. This study unveils the multifaceted role of HIF-1a in cuproptosis and demonstrates the molecular mechanism of hypoxia-promoted carcinogenesis.

引用

页码：937 / 954.e9

页数：28

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