Bclaf1 is a direct target of HIF-1 and critically regulates the stability of HIF-1α under hypoxia
Bclaf1 is a direct target of HIF-1 and critically regulates the stability of HIF-1α under hypoxia
复制标题
Bclaf1 是 HIF-1 的直接靶标，在缺氧条件下关键调节 HIF-1 α 的稳定性
DOI：
10.1038/s41388-020-1185-8
复制
发表时间：
2020-02-06
期刊：
影响因子：
8
通讯作者：
Tang, Jun
中科院分区：
文献类型：
--
作者：
Shao, Anwen;Lang, Yue;Tang, Jun
低氧应激与肿瘤进展密切相关，低氧诱导因子-1 α（HIF-1 α）是这一过程中的关键调节因子。HIF-1 α在缺氧时稳定，这是诱导基因转录所必需的，基因转录对缺氧适应很重要。Bclaf 1是一种多功能蛋白，参与肿瘤发生，然而，它在这一过程中的作用还没有得到很好的表征。在这里，我们报告Bclaf 1是HIF-1的直接转录靶点，并且在缺氧期间在多个细胞系中上调。重要的是，我们发现Bclaf 1参与了长期低氧治疗期间HIF-1 α的稳定。与对照细胞相比，Bclaf 1敲除或敲除细胞中HIF-1 α的蛋白水平和稳定性在长期低氧处理后大大受损，伴随着HIF-1靶基因转录的诱导受损。Bclaf 1敲除的HeLa细胞在小鼠异种移植物中表现出减少的肿瘤生长，其中HIF-1 α及其靶基因的表达也降低。Bclaf 1与细胞核中的HIF-1 α结合，这种相互作用是Bclaf 1在缺氧条件下稳定HIF-1 α所必需的。这些结果揭示了一个正反馈环，HIF-1-Bclaf 1，在长期缺氧条件下通过结合并保护HIF-1 α免于降解来维持HIF-1活性，并表明Bclaf 1可能通过增强HIF-1 α稳定性来促进肿瘤进展。
Hypoxic stress is intimately connected with tumor progression, with hypoxia-inducible factor-1 alpha (HIF-1 alpha) being a critical regulator in this process. HIF-1 alpha is stabilized in response to hypoxia, which is required for the induction of gene transcriptions important for hypoxic adaptation. Bclaf1 is a multifunctional protein involved in tumorigenesis, however, its role in this process is not well characterized. Here we report Bclaf1 is a direct transcriptional target of HIF-1 and upregulated in multiple cell lines during hypoxia. Importantly, we found Bclaf1 is involved in the stabilization of HIF-1 alpha during long-term hypoxic treatments. Compared with the control cells, the protein level and stability of HIF-1 alpha in Bclaf1 knockdown or knockout cells is greatly compromised after long-term hypoxic treatments, concomitant with the impaired inductions of HIF-1 target gene transcription. Bclaf1 knockout HeLa cells exhibit a reduced tumor growth in mice xenografts, in which the expressions of HIF-1 alpha and its target genes are also decreased. Bclaf1 binds to HIF-1 alpha in the nucleus, and this interaction is required for Bclaf1 to stabilize HIF-1 alpha in hypoxic condition. These results uncover a positive feedback loop, HIF-1-Bclaf1, that sustains HIF-1 activity during long-term hypoxic conditions by binding to and protecting HIF-1 alpha from degradation, and suggest that Bclaf1 may promote tumor progression by enhancing HIF-1 alpha stability.