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Medline ® Abstract for Reference 12

of 'Molecular biology and pathogenesis of von Hippel-Lindau disease'

The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion.
Koh MY, Lemos R Jr, Liu X, Powis G
Cancer Res. 2011 Jun;71(11):4015-27. Epub 2011 May 24.
Most solid tumors and their metastases experience periods of low oxygen or hypoxia, which is of major clinical significance as it promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1αand HIF-2α. The HIFs are nonredundant and regulate both overlapping and unique downstream target genes. Here, we describe a novel mechanism for the switch between HIF-1α- and HIF-2α-dependent transcription during tumor hypoxia caused by the hypoxia associated factor (HAF). HAF is overexpressed in a variety of tumors and its levels are decreased during acute hypoxia, but increased following prolonged hypoxia. We have previously identified HAF as an E3 ubiquitin ligase that binds and ubiquitinates HIF-1αby an oxygen and pVHL-independent mechanism, thus targeting HIF-1αfor proteasomal degradation. Here, we show that HAF also binds to HIF-2α, but at a different site than HIF-1α, and increases HIF-2αtransactivation without causing its degradation. HAF, thus, switches the hypoxic response of the cancer cell from HIF-1α-dependent to HIF-2α-dependent transcription and activates genes involved in invasion such as MMP9, PAI-1, and the stem cell factor OCT-3/4. The switch toHIF-2α-dependent gene expression caused by HAF also promotes an enriched tumor stem cell population, resulting in highly aggressive tumors in vivo. Thus, HAF, by causing a switch from a HIF-1α- to HIF-2α-dependent response to hypoxia, provides a mechanism for more aggressive growth of tumors under prolonged hypoxia.
Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, Texas 77230-1429, USA. mykoh@mdanderson.org