title: Transcriptional regulation of the human tumor suppressor DOK1 by E2F1.
abstract: 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.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Maha
authors.initials: M
authors.lastname: Siouda
authors.forename: Jiping
authors.initials: J
authors.lastname: Yue
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.forename: Sophie
authors.initials: S
authors.lastname: Guillermier
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Marion
authors.initials: M
authors.lastname: Creveaux
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D000077209:Decitabine; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D005047:Etoposide; D000077209:Decitabine; D008780:Methyltransferases; D001374:Azacitidine