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Signaling and Regulation

The Biphasic Role of the Hypoxia-Inducible Factor Prolyl-4-Hydroxylase, PHD2, in Modulating Tumor-Forming Potential

¹ Department of Biochemistry and Molecular Biology, ² Graduate Program in Cell and Molecular Biology, ³ Carcinogenesis Laboratory, ⁴ Diagnostic Center for Population and Animal Health, ⁵ Department of Pathobiology and Diagnostic Investigation, ⁶ Department of Microbiology and Molecular Genetics, ⁷ National Food Safety and Toxicology Center; and ⁸ Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan

Requests for reprints: John J. LaPres, Department of Biochemistry and Molecular Biology, 224 Biochemistry Building, Michigan State University, East Lansing, MI 48824-1319. Phone: 517-432-9282; Fax: 517-353-9334. E-mail: lapres{at}msu.edu

Hypoxia is a common feature of solid tumors. The cellular response to hypoxic stress is controlled by a family of prolyl hydroxylases (PHD) and the transcription factor hypoxia-inducible factor 1 (HIF1). To investigate the relationship between PHD and HIF1 activity and cellular transformation, we characterized the expression levels of PHD isoforms across a lineage of cell strains with varying transformed characteristics. We found that PHD2 is the primary functional isoform in these cells and its levels are inversely correlated to tumor-forming potential. When PHD2 levels were altered with RNA interference in nontumorigenic fibroblasts, we found that small decreases can lead to malignant transformation, whereas severe decreases do not. Consistent with these results, direct inhibition of PHD2 was also shown to influence tumor-forming potential. Furthermore, we found that overexpression of PHD2 in malignant fibroblasts leads to loss of the tumorigenic phenotype. These changes correlated with HIF1 activity, glycolytic rates, vascular endothelial growth factor expression, and the ability to grow under hypoxic stress. These findings support a biphasic model for the relationship between PHD2 activity and malignant transformation. (Mol Cancer Res 2008;6(5):829–42)