High endogenous levels of
aryl hydrocarbon receptor (AhR) contribute to
hypoxia signaling pathway inhibition following exposure to the potent AhR
ligand benzo[a]pyrene (B[a]P) and could alter cellular homeostasis and disease condition. Increasing evidence indicates that AhR might compete with
AhR nuclear translocator (ARNT) for complex formation with
hypoxia-inducible factor-1α (HIF-1α) for transactivation, which could alter several physiological variables.
Nuclear receptor coactivator 2 (NcoA2) is a transcription coactivator that regulates
transcription factor activation and inhibition of basic helix-loop-helix Per (Period)-ARNT-SIM (single-minded) (bHLH-PAS) family
proteins, such as HIF-1α, ARNT, and AhR, through
protein-
protein interactions. In this study, we demonstrated that both
hypoxia and
hypoxia-mimic conditions decreased NcoA2
protein expression in HEK293T cells.
Hypoxia response element (HRE) and
xenobiotic-responsive
element (XRE) transactivation also were downregulated with NcoA2 knockdown under hypoxic conditions. In addition, B[a]P significantly decreased NcoA2
protein expression be accompanied with AhR degradation. We next evaluated whether the absence of AhR could affect NcoA2
protein function under
hypoxia-mimetic conditions. NcoA2 and HIF-1α nuclear localization decreased in both B[a]P-pretreated and AhR-knockdown HepG2 cells under
hypoxia-mimic conditions. Interestingly, NcoA2 overexpression downregulated HRE transactivation by competing with HIF-1α and AhR to form
protein complexes with ARNT. Both NcoA2 knockdown and overexpression inhibited endothelial cell tube formation in vitro. We also demonstrated using the in vivo plug assay that NcoA2-regulated vascularization decreased in mice. Taken together, these results revealed a biphasic role of NcoA2 between AhR and hypoxic conditions, thus providing a novel mechanism underlying the cross talk between AhR and
hypoxia that affects disease development and progression.