Hypoxia-inducible factor-1α obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of β-catenin

Although a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1 alpha (HIF-1 alpha), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1 alpha. Here, we addressed the functional significance of the hARD1-HIF-1 alpha interaction. Because hARD1 acetylates and activates beta-catenin, we examined whether HIF-1 alpha regulates the hARD1-mediated activation of Writ signaling. It was found that HIF-1 alpha binds hARD1 through the oxygen-dependent degradation domain and, in so doing, dissociates hARD1 from beta-catenin, which prevents beta-catenin acetylation. In LiCl-stimulated HEK293 or cancer cell lines with active Writ signaling, beta-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1 alpha. Moreover, HIF-1 alpha disruption of hARD1/beta-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21(cip1) induction. In addition, we confirmed that the HIF-1 alpha NH2 terminal inactivates TCF4 by directly binding beta-catenin. In conclusion, HIF-1 alpha was found to inactivate the Wnt signaling by binding to hARD1 or beta-catenin, which may contribute to the hypoxia-induced growth arrest of tumor cells.