Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin.

Although a splice variant of mouse mARD1s was found to acetylate and destabilize hypoxia-inducible factor-1alpha (HIF-1alpha), human hARD1 has no such activities. Nonetheless, hARD1 has been reported to bind directly with HIF-1alpha. Here, we addressed the functional significance of the hARD1-HIF-1alpha interaction. Because hARD1 acetylates and activates beta-catenin, we examined ...
whether HIF-1alpha regulates the hARD1-mediated activation of Wnt signaling. It was found that HIF-1alpha 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 Wnt signaling, beta-catenin acetylation and activity were suppressed in hypoxia, and these suppressions were mediated by HIF-1alpha. Moreover, HIF-1alpha disruption of hARD1/beta-catenin repressed TCF4 activity, resulting in c-Myc suppression and p21(cip1) induction. In addition, we confirmed that the HIF-1alpha NH(2) terminal inactivates TCF4 by directly binding beta-catenin. In conclusion, HIF-1alpha 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.
Mesh Terms:
Acetylation, Acetyltransferases, Cell Hypoxia, Cell Proliferation, Cells, Cultured, Gene Expression Regulation, HCT116 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Models, Biological, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Protein Binding, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Signal Transduction, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Wnt Proteins, beta Catenin
Cancer Res
Date: Jul. 01, 2008
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