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Molecular Cancer Research 2:89-95 (2004)
© 2004 American Association for Cancer Research

Cancer Genes and Genomics

Inhibition of Hypoxia-Inducible Factor Is Sufficient for Growth Suppression of VHL−/− Tumors1

Michael Zimmer, Darrell Doucette, Naila Siddiqui and Othon Iliopoulos

Hematology-Oncology Unit, Department of Medicine, Massachusetts General Hospital and the Massachusetts General Hospital Cancer Center, Boston, MA

Requests for reprints: Othon Iliopoulos, Massachusetts General Hospital, 55 Fruit Street, GRJ904, Boston, MA 02114. Phone: (617) 724-3404; Fax: (617) 726-8623. E-mail: oiliopoulos{at}partners.org

The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate receptor for the mammalian SCF-2 E3 ubiquitin ligase complex that targets several substrates for ubiquitination and proteasomal degradation. Among these targets are the {alpha}-regulatory subunits of the hypoxia-inducible factor (HIF). VHL−/− cells constitutively overexpress hypoxia-inducible genes through both transcriptional and posttranscriptional mechanisms and form tumors when injected into nude mice. Reintroduction of pVHL into VHL−/− cell lines restores normal oxygen-dependent regulation of these genes and suppresses tumor formation in the mouse xenograft assay. We report here that short hairpin RNA-mediated inactivation of HIF phenocopies the effects of pVHL reintroduction with respect to decreased expression of hypoxia-inducible genes, decreased ability to promote vascular endothelial cell proliferation in vitro, and tumor growth suppression in vivo. In addition, HIF inactivation abrogated the cellular response to hypoxia, indicating that HIF is the only pVHL target required for this response. These data suggest that deregulation of hypoxia-inducible genes in VHL−/− cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target.




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Copyright © 2004 by the American Association for Cancer Research.