Hypoxia-Dependent Regulation of β-Catenin by the Orphan Nuclear Receptor Nur77

Abstract

It has become increasingly recognized the importance of tumor microenvironment in cancer initiation and progression. The microenvironment of solid tumors contains regions of poor oxygenation as a result of hypoxia. Nur77, an orphan nuclear receptor, can play multiple roles in cell survival and apoptosis in a cell-context dependent manner. Nur77 is activated in colon cancers and in the large majority of cases by an increased or altered expression. Since Nur77 gene amplification is a rare event, the mechanisms underlying Nur77 protein expression in colon tumors remain obscure. Here we showed that hypoxia activated the expression of Nur77, resulting in higher levels of Nur77 protein and mRNA. We also showed for the first time that Nur77 overexpression resulted in an upregulation of β-catenin expression under hypoxia. Knockdown of Nur77 using small interfering RNA significantly inhibited the activation of β-catenin, confirming that the effect was Nur77 specific. Using paired colon carcinoma cell lines and various mutant constructs, we provided evidence that the Nur77-induced β-catenin expression at the levels achieved by hypoxia was independent of both p53 and APC, which are components of two major pathways for β-catenin degradation. Moreover, Nur77 lacking the DNA binding domain failed to regulate the expression of β-catenin, suggesting that nuclear Nur77 is important for this regulation. These results may provide a molecular basis for overexpression of Nur77 in colon cancer and a novel regulatory mechanism that regulates cell survival and death.