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Hypoxia-Inducible Factor-1 Obstructs a Wnt Signaling Pathway by Inhibiting the hARD1-Mediated Activation of β-Catenin

Departments of ¹ Pharmacology and ² Physiology, ³ Cancer Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul, Korea

Requests for reprints: Jong-Wan Park, Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea. Phone: 82-2-740-8289; Fax: 82-2-745-7996; E-mail: parkjw{at}snu.ac.kr.

Key Words: Hypoxia/HIF-1 • hARD1 • β-catenin • TCF4

Although a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1 (HIF-1), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1. Here, we addressed the functional significance of the hARD1–HIF-1 interaction. Because hARD1 acetylates and activates β-catenin, we examined whether HIF-1 regulates the hARD1-mediated activation of Wnt signaling. It was found that HIF-1 binds hARD1 through the oxygen-dependent degradation domain and, in so doing, dissociates hARD1 from β-catenin, which prevents β-catenin acetylation. In LiCl-stimulated HEK293 or cancer cell lines with active Wnt signaling, β-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1. Moreover, HIF-1 disruption of hARD1/β-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21^cip1 induction. In addition, we confirmed that the HIF-1 NH₂ terminal inactivates TCF4 by directly binding β-catenin. In conclusion, HIF-1 was found to inactivate the Wnt signaling by binding to hARD1 or β-catenin, which may contribute to the hypoxia-induced growth arrest of tumor cells. [Cancer Res 2008;68(13):5177–84]