Abstract
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.
Highlights
Hypoxia, or reduced oxygen availability, is an important developmental cue in multicellular organisms, but it is involved in a number of human pathologies [1,2]
As we had observed hypoxia inducible factor (HIF)-1-dependent increases in mRNA and protein of KDM2A in hypoxia, end, HIF-1 subunits were depleted by siRNA from cells and levels of RNA polymerase II present at we investigated the functional significance of HIF-1 presence at the KDM2A promoter
We have identified that the KDM2 family of JmjC demethylases is responsive to
Summary
Reduced oxygen availability, is an important developmental cue in multicellular organisms, but it is involved in a number of human pathologies [1,2]. Cells orchestrate a tightly controlled and coordinated response, mostly dependent on transcriptional changes [3]. In the centre stage of such a response, stands the transcription factor family, hypoxia inducible factor (HIF). While HIF-1β protein levels remain largely unchanged in hypoxia, HIF-α levels are extremely sensitive to change in oxygen availability. Oxygen sensitivity is conferred to the HIF system, via the action of a class of dioxygenases called prolyl hydroxylases (PHDs). PHDs require molecular oxygen, 2-oxoglutarate, and iron as cofactors to perform proline hydroxylation of their targets [5]
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