Nur77 Dependent Induction Of HIF1? Degradation By Small Molecule XS-170

Hypoxia-inducible factor-1?(HIF1?)plays a central role in oxygen homeostasis.It regulates the expression of more than 70 target genes involved in tumor growth,metastasis,invasion,angiogenesis,metabolic adaptation.Orphan nuclear receptor Nur77 belongs to the nuclear receptor superfamily,and plays an important role in numerous biological processes including cellular proliferation and growth,apoptosis,and immune response in normal and malignant cells.Previous studies demonstrated that Nur77 could enhance the transcriptional activity of HIF1? by inhibiting pVHL-mediated proteasome-mediated HIF1? degradation.Thus,identification of Nur77 modulators capable of inhibiting Nur77-dependent HIF1? stability may lead to the development of novel cancer therapeutics.Here,we demonstrate that XS-170,a new small molecule recently identified in our lab,can bind Nur77 to induce HIFla degradation.In vitro study showed that XS-170 inhibited the expression of HIF1? protein in a Nur77 dependent manner under hypoxia.By using PyMT transgenic breast cancer mice model,we found that XS-170 could significantly inhibit the growth of breast tumors,which was accompanied with inhibition of the expression of HIF1? and its downstream target gene VEGF.Mechanistically,our data demonstrated that induction of HIF1? degradation by XS-170 in hypoxia could be attributed to its promotion of Nur77 poly-ubiquitination and degradation.Furthermore,we found that XS-170 could enhance Nur77 interaction with VHL known to recruit E3 ubiquitin ligase complex.Together,our results identify XS-170 as a promising lead for breast cancer therapy and provide important insight into its mechanism of action.