Hypoxic microenvironments are frequently found in solid tumors as a result of an imbalance between O2 supply and consumption. Hypoxia inducible factors-mediated hypoxia transcriptional responses have been shown to drive malignant progression by activation of angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or to escape their O2-deficient microenvironments. HIF1( and HIF2( are the two major transcription factors responding to low oxygen (hypoxia) in solid tumors. The two proteins are stabilized by hypoxia in a similar fashion, utilize the same binding partner (HIF1(), and regulate some common hypoxia- responsive genes. In spite of these similarities, HIF2( (but not HIF1() is associated with human tumors and promotes tumor growth in several mouse models. HIF2( promotes tumor growth by activating a group of cancer promoting factors not shared with HIF1(. HIF2( activates its unique genes by interacting with other transcription factors not shared with HIF1(. The long-term goal of my laboratory is to elucidate the regulatory mechanisms controlling HIF1( and HIF2('s transcriptional activity as a prerequisite to therapeutic strategies that can be used in solid tumor treatment. The specific objective of this application is to characterize the role of the basic-helix-loop-helix-leucine zipper transcription factor, upstream stimulatory factor 2 (USF2) in regulating HIF2( transcriptional activity. Our hypothesis is that USF2 is required for HIF2( to activate its target genes and for HIF2( to promote tumorigenesis. This hypothesis is based on the following observations. First, HIF2( and USF2 share a large number of common target genes. An example of such gene is the plasminogen activator inhibitor 1 (PAI1). Second, we have shown that USF2 silencing decreased hypoxic induction of HIF2(, but not HIF1( target genes. Finally, we showed that USF2 and HIF2( activated PAI-1 promoter synergistically while USF2 dominant-negative inhibited HIF2(-mediated PAI-1 promoter activation. To test the hypothesis, we propose the following three specific aims: 1. Test the requirement of USF2 for HIF2( and/or HIF1( to activate their target gene expression under hypoxia. 2. Characterize the mechanism of USF2 in regulating the HIF2( target PAI-1 and others. 3. Analyze the function of USF2 in HIF2(-mediated tumorigenesis. HIF2( plays a critical role in solid tumor progression. However, the factors regulating its transcription activity are largely unknown. Using a combination of biochemical, genetic, and molecular biology system, the proposed experiments will test USF2 as an important HIF2( co-activator, define USF2-dependent HIF2( target genes, as well as the functional importance of these HIF2( target genes in HIF2(-mediated tumor growth. These results will lay a foundation to specifically block HIF2( activity for solid tumor treatment.

Public Health Relevance

Cancer is one of the major causes of mortality in the USA, it was projected that in 2006, there would be 564,830 cancer deaths overall in the USA according a NCI cancer trends progress report-2005. Solid tumors such as breast, prostate, lung, and colon/rectum accounted for more than half of all cancer deaths in the United States. One of the common features of the solid tumors is lack of oxygen supply (hypoxia). Tumor cells in the oxygen-deficient regions turn on hypoxia inducible transcription factor (HIF) activity. HIF allows tumor cells to survive and even to grow under such harsh environment by promoting blood vessel formation, ATP (food for cell) generation, and expression of survival factors. Thus, HIF is good for tumor growth, but bad for our human being. Thus our research on controlling HIF activity has broad impact for all solid tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Mietz, Judy
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University of Colorado Denver
Schools of Dentistry
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Sena, Johnny A; Wang, Liyi; Pawlus, Matthew R et al. (2014) HIFs enhance the transcriptional activation and splicing of adrenomedullin. Mol Cancer Res 12:728-41
Storti, Federica; Santambrogio, Sara; Crowther, Lisa M et al. (2014) A novel distal upstream hypoxia response element regulating oxygen-dependent erythropoietin gene expression. Haematologica 99:e45-8
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Pawlus, Matthew R; Wang, Liyi; Murakami, Aya et al. (2013) STAT3 or USF2 contributes to HIF target gene specificity. PLoS One 8:e72358
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