ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment

Hypoxia is an established hallmark of tumorigenesis. HIF-1α activation may be the prime driver of adaptive regulation of tumor cells reacting to hypoxic conditions of the tumor microenvironment. Here, we report a novel regulatory mechanism in charge of the fundamental stability of HIF-1α in solid tumor. Under hypoxic conditions, the checkpoint kinase CHK2 binds to HIF-1α and inhibits its ubiquitination, which is highly likely due to phosphorylation of a threonine residue (Thr645), a formerly uncharacterized site within the inhibitory domain. Meanwhile, HIF-1α phosphorylation induced by CHK2 promotes complex formation between HIF-1-α and the deubiquitination enzyme USP7, increasing stability under hypoxic conditions. This novel modification of the crosstalk between phosphorylation and ubiquitination of HIF-1α mediated by CHK2 enriches the post-translational modification spectrum of HIF-1α, thus offering novel insights into potential anti-angiogenesis therapies.

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Publication Details

Journal
Oncogene
Published
2025-03-08
DOI
https://doi.org/10.1038/s41388-025-03336-w
Citations
7
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
Field-Weighted Citation Impact
6.55

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article

ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment

Xuan Wu, Sunrun Cao, Ning Bai, Xiaoyu Song et al.
7 citations
Oncogene
Cancer, Hypoxia, and Metabolism
6.55
article

ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment

Xuan Wu, Sunrun Cao, Ning Bai, Xiaoyu Song, Xiaoxun Wang, Bo Jiang, Mingfang Zhao, Liu Cao, Chen Sun, Ming Bai, Chunlu Li, Peng Xu, Qiqiang Guo, Rong Cheng, Na Li
article en
7 citations

Abstract

Hypoxia is an established hallmark of tumorigenesis. HIF-1α activation may be the prime driver of adaptive regulation of tumor cells reacting to hypoxic conditions of the tumor microenvironment. Here, we report a novel regulatory mechanism in charge of the fundamental stability of HIF-1α in solid tumor. Under hypoxic conditions, the checkpoint kinase CHK2 binds to HIF-1α and inhibits its ubiquitination, which is highly likely due to phosphorylation of a threonine residue (Thr645), a formerly uncharacterized site within the inhibitory domain. Meanwhile, HIF-1α phosphorylation induced by CHK2 promotes complex formation between HIF-1-α and the deubiquitination enzyme USP7, increasing stability under hypoxic conditions. This novel modification of the crosstalk between phosphorylation and ubiquitination of HIF-1α mediated by CHK2 enriches the post-translational modification spectrum of HIF-1α, thus offering novel insights into potential anti-angiogenesis therapies.

OncogeneVol. 44(21)
Shenyang Medical College (CN), Ministry of Education (SA), Linyi People's Hospital (CN), First Hospital of China Medical University (CN), Ministry of Education (KN), China Medical University (CN)
National Natural Science Foundation of China, Department of Science and Technology of Liaoning Province, National Key Research and Development Program of China
Openalex Percentile: Top 3%
Cancer, Hypoxia, and Metabolism
6.55
DOIOpen Access PDFOpenAlex
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