KDM2 Family Members are Regulated by HIF-1 in Hypoxia.
KDM2 Family Members are Regulated by HIF-1 in Hypoxia.
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作者：
Batie M;Druker J;D'Ignazio L;Rocha S
在许多人类疾病中，缺氧不仅是一种发育线索，而且是一种应激和病理刺激。细胞水平对低氧的反应依赖于转录因子家族低氧诱导因子(HIF)的活性。HIF-1负责急性反应，并反式激活多种参与细胞代谢、细胞死亡和细胞生长的基因。在这里，我们发现低氧导致人类赖氨酸(K)特异性脱甲基酶2(KDM2)家族成员KDM2a和Kdm2b以及果蝇KDM2(一种组蛋白和蛋白质去甲基酶)的mRNA水平升高。在人类细胞中，缺氧时KDM2家族成员的mRNA水平受HIF-1的调节，而不受HIF-2的调节。有趣的是，只有KDM2a蛋白水平以HIF-1依赖的方式显著诱导，而Kdm2b蛋白以细胞类型依赖的方式变化。重要的是，我们证明在人类细胞中，KDM2A受缺氧和HIF-1的调节发生在启动子水平，HIF-1与KDM2A启动子结合是RNA聚合酶II招募所必需的。综上所述，这些结果表明KDM2是一个新的HIF靶点，可以帮助协调细胞对低氧的反应。此外，这些结果可能解释了为什么KDM2水平在人类癌症中经常被解除调控。
Hypoxia is not only a developmental cue but also a stress and pathological stimulus in many human diseases. The response to hypoxia at the cellular level relies on the activity of the transcription factor family, hypoxia inducible factor (HIF). HIF-1 is responsible for the acute response and transactivates a variety of genes involved in cellular metabolism, cell death, and cell growth. Here, we show that hypoxia results in increased mRNA levels for human lysine (K)-specific demethylase 2 (KDM2) family members, KDM2A and KDM2B, and also for Drosophila melanogaster KDM2, a histone and protein demethylase. In human cells, KDM2 family member’s mRNA levels are regulated by HIF-1 but not HIF-2 in hypoxia. Interestingly, only KDM2A protein levels are significantly induced in a HIF-1-dependent manner, while KDM2B protein changes in a cell type-dependent manner. Importantly, we demonstrate that in human cells, KDM2A regulation by hypoxia and HIF-1 occurs at the level of promoter, with HIF-1 binding to the KDM2A promoter being required for RNA polymerase II recruitment. Taken together, these results demonstrate that KDM2 is a novel HIF target that can help coordinate the cellular response to hypoxia. In addition, these results might explain why KDM2 levels are often deregulated in human cancers.