ROS-ATM-CHK2 axis stabilizes HIF-1α and promotes tumor angiogenesis in hypoxic microenvironment
Ming Bai, Peng 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
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.