Abstract
Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of κ-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk.
Highlights
NF-κB Subunits and Signalling PathwaysNF-κB is the collective name of a family of transcription factors initially discovered in 1986 by Ranjan Sen and David Baltimore as a Nuclear Factor binding to the enhancer element of the immunoglobulin κ light-chain of activated B cells [1]
A recent study highlighted the importance of intestinal epithelial Hypoxia Inducible Factor (HIF)-2α in the recruitment of neutrophils to colon tumour sites, supporting its prominent role in the inflammatory microenvironment [83]. Another example of hypoxia and inflammation crosstalk in cancer is observed in Hepatocellular Carcinoma (HCC), where TNF-α is one of the cytokines constantly activated by NF-κB, through the Tumour Associated Macrophages (TAMs)
The authors of this study suggested a Prolyl Hydroxylases (PHDs) prolyl hydroxylase dependent mechanism, providing evidence that IKKβ is a potential PHD target through the identification of conserved PHD prolyl hydroxylation motif, which is required for the hypoxia induction of IKKβ levels
Summary
NF-κB is the collective name of a family of transcription factors initially discovered in 1986 by Ranjan Sen and David Baltimore as a Nuclear Factor binding to the enhancer element of the immunoglobulin κ light-chain of activated B cells [1]. N-terminal harbouring a Rel Homology Domain (RHD) This is essential to mediate DNA binding to κb sites in enhancers/promoters of target genes, as well as to dimerise with other subunits. In the canonical NF‐κB signalling pathway, the binding of Tumour kinases, serving as activation leading the phosphorylation. Phosphorylation of IκBα on serines 32 and 36 is the key prerequisite for the lysine-48 which, in quiescent cells, hold the NF‐κB subunits inactive in the cytoplasm. On the other and subsequent degradation mediated by the proteasomal machinery This event makes the NF‐κB hand,dimers the non-canonical pathway onDNA activation of different free to translocate intosignalling the nucleus, binding depends the cognate sequence to regulatemembrane gene transcription. Upon binding of the SCF ubiquitin ligase, the inhibitor ankyrin repeat domain of p100 is subject activetoform p52 originates andThus, associates with RelB, asoriginates transcriptional activator heterodimer proteasomal processing. We will discuss the role of NF-κB in cancer, focusing on how this transcription factor can be induced by hypoxia, and modulated by HIF, in a variety of tumour contexts
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
