Transcriptional Regulation of the Human Tumor Suppressor DOK1 by E2F1
| Autor: | Marion Creveaux, Maha Siouda, Sophie Guillermier, Jiping Yue, Bakary S. Sylla, Ruchi Shukla, Massimo Tommasino, Zdenko Herceg, Rosita Accardi |
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| Rok vydání: | 2012 |
| Předmět: |
Transcriptional Activation
endocrine system Apoptosis Biology Decitabine Response Elements Cell Line Epigenetics of physical exercise Transcription (biology) Cell Line Tumor Transcriptional regulation Humans E2F1 Gene silencing Gene Silencing Molecular Biology Cell Proliferation Etoposide RNA-Binding Proteins E2F1 Transcription Factor Promoter Methyltransferases Articles Cell Biology DNA Methylation Chromatin Assembly and Disassembly Phosphoproteins Antineoplastic Agents Phytogenic DNA-Binding Proteins HEK293 Cells DNA methylation Azacitidine Cancer research biological phenomena cell phenomena and immunity DNA Damage |
| Zdroj: | Molecular and Cellular Biology. 32:4877-4890 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.01050-12 |
| Popis: | The expression of the tumor suppressor DOK1 is repressed in a variety of human tumors as a result of hypermethylation of its promoter region. However, the molecular mechanisms by which DOK1 expression is regulated have been poorly investigated. Here, we show that the expression of DOK1 is regulated mainly by the transcription factor E2F1. We identified three putative E2F1 response elements (EREs) in the DOK1 promoter region. E2F1 had a relatively higher binding affinity for the ERE located between bp -498 and -486 compared with the other two EREs. E2F1 gene silencing strongly inhibited DOK1 expression. E2F1-driven DOK1 transcription occurred in the presence of cellular stresses, such as accumulation of DNA damage induced by etoposide. DOK1 silencing promoted cell proliferation and protected against etoposide-induced apoptosis, indicating that DOK1 acts as a key mediator of cellular stress-induced cell death. Most importantly, we observed that DNA methylation of the DOK1 core promoter region found in head and neck cancer cell lines hampered the recruitment of E2F1 to the DOK1 promoter and compromised DOK1 expression. In summary, our data show that E2F1 is a key factor in DOK1 expression and provide novel insights into the regulation of these events in cancer cells. |
| Databáze: | OpenAIRE |
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