A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.
A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.
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DOI：
10.1038/ncb3445
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发表时间：
2017-01
影响因子：
21.3
通讯作者：
Lin HK
中科院分区：
文献类型：
--
作者：
Rezaeian AH;Li CF;Wu CY;Zhang X;Delacerda J;You MJ;Han F;Cai Z;Jeong YS;Jin G;Phan L;Chou PC;Lee MH;Hung MC;Sarbassov D;Lin HK
了解低氧如何稳定和激活细胞核中的HIF1α以及相关的致癌信号，可以彻底改变癌症的靶向治疗。在这里，我们发现组蛋白H2AX通过作为HIF1α信号的关键调节因子而显示出致癌活性。在低氧条件下，H_2AX与HIF1α相互作用并阻止其降解和核输出，以一种不依赖于VHL的方式进行转录激活。我们发现，由缺氧诱导的TRAF6和ATM的E3连接酶活性严格介导的H_2AX的单素化和磷酸化，对HIF1α驱动的肿瘤发生起着关键的调控作用。重要的是，TRAF6和HIF1HAX在人类乳腺癌中过表达，与γα信号的激活相关，并预测转移结果。因此，TRAF6和H_2AX的过表达以及γH_2AX介导的HIF_1α在细胞核内的聚集导致HIF_1α的过度激活，从而导致肿瘤的发生、糖酵解和转移。我们的发现表明，TRAF6介导的单泛素化和随后的H_2AX磷酸化可能成为癌症诊断和治疗的潜在手段。
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals can revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with and prevents HIF1α from degradation and nuclear export upon hypoxia for transcriptional activation in a VHL-independent manner. We show that monoubiquitination and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumourigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumourigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated monoubiquitination and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.