NF-κB is a Central Regulator of Hypoxia-Induced Gene Expression

Hypoxia is both a physiological and pathological signal in cells. Changes in gene expression play a critical role in the cellular response to hypoxia, enabling cells to adapt to reduced oxygen availability by regulating metabolism, angiogenesis, and survival pathways. These changes are primarily mediated by the HIF family of transcription factors, however other transcription factors such as NF-κB, are also activated in the hypoxic response. Although NF-κB is known to be activated under hypoxic conditions the extent of NF-κB contributions to the hypoxic response remains poorly understood. In this study we analyse hypoxia-induced NF-κB dependent gene expression, to define the NF-κB-dependent hypoxic signature. Our analysis reveals that a significant proportion of hypoxia-induced gene expression changes are NF-κB dependent, with majority of the hypoxia downregulated genes requiring NF-κB for their repression. We show that, while the NF-κB-mediated hypoxic response may vary between cell types, there are a core subset of hypoxia inducible genes that require NF-κB across multiple cell backgrounds. We demonstrate that NF-κB is critical for reactive oxygen species (ROS) generation and regulation of genes involved in oxidative phosphorylation under hypoxic conditions. This work highlights that NF-κB has a central role in hypoxia response, regulating a broader set of genes than previously thought, providing new understanding into the gene expression regulation by hypoxia and NF-κB.