2. Academic Validation
  3. Multi-level interaction between HIF and AHR transcriptional pathways in kidney carcinoma

Multi-level interaction between HIF and AHR transcriptional pathways in kidney carcinoma

  • Life Sci Alliance. 2023 Feb 1;6(4):e202201756. doi: 10.26508/lsa.202201756.
Véronique N Lafleur 1,  Silvia Halim 1,  Hani Choudhry 2,  Peter J Ratcliffe 3 4,  David R Mole 5
Affiliations

Affiliations

  • 1 https://ror.org/052gg0110 NDM Research Building, University of Oxford, Old Road Campus, Oxford, UK.
  • 2 Department of Biochemistry, Faculty of Science, Center of Innovation in Personalized Medicine, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia.
  • 3 https://ror.org/052gg0110 Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Oxford, UK.
  • 4 The Francis Crick Institute, London, UK.
  • 5 https://ror.org/052gg0110 NDM Research Building, University of Oxford, Old Road Campus, Oxford, UK david.mole@ndm.ox.ac.uk.
PMID: 36725335 DOI: 10.26508/lsa.202201756
Abstract

Hypoxia-inducible factor (HIF) and Aryl Hydrocarbon Receptor (AHR) are members of the bHLH-PAS family of transcription factors that underpin cellular responses to oxygen and to endogenous and exogenous ligands, respectively, and have central roles in the pathogenesis of renal Cancer. Composed of heterodimers, they share a common HIF-1β/ARNT subunit and similar DNA-binding motifs, raising the possibility of crosstalk between the two transcriptional pathways. Here, we identify both general and locus-specific mechanisms of interaction between HIF and AHR that act both antagonistically and cooperatively. Specifically, we observe competition for the common HIF-1β/ARNT subunit, in cis synergy for chromatin binding, and overlap in their transcriptional targets. Recently, both HIF and AHR inhibitors have been developed for the treatment of solid tumours. However, inhibition of one pathway may promote the oncogenic effects of the other. Therefore, our work raises important questions as to whether combination therapy targeting both of these pro-tumourigenic pathways might show greater efficacy than targeting each system independently.

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