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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月8日

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  • Ming Bai,
  • Pengzhi Xu,
  • Rong Cheng,
  • Na Li,
  • Sunrun Cao,
  • Qiqiang Guo,
  • Xiaoxun Wang,
  • Chunlu Li,
  • Ning Bai,
  • Bo Jiang,
  • Xuan Wu,
  • Xiaoyu Song,
  • Chen Sun,
  • Mingfang Zhao,
  • Liu Cao

摘要

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.