KDM2 Family Members are Regulated by HIF-1 in Hypoxia

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.

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

“…Interestingly, KDM2A is NF-κB inducible [95] as well as hypoxia inducible in HIF-1 dependent manner, as recently shown by our group [69]. This represents another feedback loop of NF-κB regulating its own activity, and may confer another level of crosstalk between low oxygen availability and NF-κB function.…”

“…Interestingly, many of these enzymes are hypoxia inducible (reviewed in [55]), with some, including Lysine (K)-specific demethylase 4B (KDM4B), KDM4C, KDM5B, KDM3A, KDM2A and KDM2B, being HIF targets [64][65][66][67][68][69]. This may point to negative feedback mechanism to help regulate histone methylation in a JmjC histone demethylase compromised environment, and possibly help the cell reset its oxygen sensing and response mechanisms after prolonged hypoxia and/or restoration of normoxia, as is seen with PHD regulation of HIF.…”

“…This represents another feedback loop of NF-κB regulating its own activity, and may confer another level of crosstalk between low oxygen availability and NF-κB function. KDM2B, the other member of KDM2 family member, is also hypoxia and NF-κB inducible [69,100]; however, it is currently unknown if this enzyme influences NF-κB activity. Another NF-κB induced JmjC enzyme, KDM6B, promotes activation of a subset of genes in LPS activated macrophages in a histone demethylase independent manner [101].…”

Hypoxia and Chromatin, a Focus on Transcriptional Repression Mechanisms

“…Many JmjC histone demethylases are transcriptionally upregulated in hypoxia some of which are direct HIF target genes (reviewed in [53,64]). It is speculated that upregulation of JmjC histone demethylases in response to low oxygen may be a feedback mechanism to help maintain to retain histone methylation status of the cell.…”

Hypoxia induces rapid changes to histone methylation reprogramming chromatin for the cellular response

“…Surprisingly, depletion of HIF 1b resulted in even higher levels of histone methylation marks in hypoxia, demonstrating the HIF is not required for the changes observed in hypoxia. Increased levels of histone marks in the absence of HIF 1b could be due to reduced levels of several JmjC histone demethylases since these are known to be 25 direct targets of the HIF 1 complex (10,19). To further investigate the involvement of HIF in our mechanism, we used the selective chemical probe VH298 (20), which inhibits VHL without altering PHD or other dioxygenases functions in cells (20).…”