Interaction of HIF and USF signaling pathways in human genes flanked by hypoxia-response elements and E-box palindromes
| Autor: | Claudia Setzer, Max Gassmann, Daniela Wichmann, Dheeraj A. Shinde, Hubert Rehrauer, Daniel P. Stiehl, Pavel Hradecky, Thomas A. Gorr, Junmin Hu |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Lactate dehydrogenase A USF1 E-box Response Elements Transfection Upstream Stimulatory Factor E-Box Elements 03 medical and health sciences 0302 clinical medicine Transcription (biology) Cell Line Tumor Prohibitins Humans education Molecular Biology Transcription factor 030304 developmental biology 0303 health sciences education.field_of_study biology Inverted Repeat Sequences Molecular biology 3. Good health Chromatin Oncology 030220 oncology & carcinogenesis Cancer cell biology.protein Upstream Stimulatory Factors Female Hypoxia-Inducible Factor 1 HeLa Cells Signal Transduction |
| Zdroj: | Molecular cancer research : MCR |
| DOI: | 10.1158/1541-7786.MCR-11-0090 |
| Popis: | Rampant activity of the hypoxia-inducible factor (HIF)-1 in cancer is frequently associated with the malignant progression into a harder-to-treat, increasingly aggressive phenotype. Clearly, anti-HIF strategies in cancer cells are of considerable clinical interest. One way to fine-tune, or inhibit, HIF's transcriptional outflow independently of hydroxylase activities could be through competing transcription factors. A CACGTG-binding activity in human hepatoma cells was previously found to restrict HIF's access to hypoxia response cis-elements (HRE) in a Daphnia globin gene promoter construct (phb2). The CACGTG factor, and its impact on hypoxia-responsive human genes, was analyzed in this study by genome-wide computational scans as well as gene-specific quantitative PCR, reporter and DNA-binding assays in hepatoma (Hep3B), cervical carcinoma (HeLa), and breast carcinoma (MCF7) cells. Among six basic helix-loop-helix transcription factors known to target CACGTG palindromes, we identified upstream stimulatory factor (USF)-1/2 as predominant phb2 CACGTG constituents in Hep3B, HeLa, and MCF7 cells. Human genes with adjacent or overlapping HRE and CACGTG motifs included with lactate dehydrogenase A (LDHA) and Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3) hypoxia-induced HIF-1 targets. Parallel recruitment of HIF-1α and USF1/2a to the respective promoter chromatin was verified for all cell lines investigated. Mutual complementing (LDHA) or moderating (BNIP3) cross-talk was seen upon overexpression or silencing of HIF-1α and USF1/2a. Distinct (LDHA) or overlapping (BNIP3) promoter-binding sites for HIF-1 and USFs were subsequently characterized. We propose that, depending on abundance or activity of its protein constituents, O2-independent USF signaling can function to fine-tune or interfere with HIF-mediated transcription in cancer cells. Mol Cancer Res; 9(11); 1520–36. ©2011 AACR. |
| Databáze: | OpenAIRE |
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