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

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 en-dogenous and exogenous ligands, respectively, and have central roles in the pathogenesis of renal cancer. Composed of hetero-dimers, they share a common HIF-1 beta/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-1 beta/ARNT subunit, in cis synergy for chromatin binding, and overlap in their tran-scriptional 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 tar-geting each system independently.

Automated summary

Hypoxia-inducible factor (HIF) and aryl hydrocarbon receptor (AHR) are transcription factors that play central roles in the pathogenesis of renal cancer. They have both antagonistic and cooperative interactions, including competition for a common subunit, synergy in chromatin binding, and overlapping transcriptional targets. Inhibition of one pathway may promote the oncogenic effects of the other, suggesting that combination therapy targeting both pathways might be more effective.