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We previously reported that the <jats:italic>DOK1<\/jats:italic> gene can be mutated and its expression down\u2010regulated in human malignancies. However, the mechanism underlying <jats:italic>DOK1<\/jats:italic> silencing remains largely unknown. We show here that unscheduled silencing of <jats:italic>DOK1<\/jats:italic> expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. <jats:italic>DOK1<\/jats:italic> was found to be silenced in nine head and neck cancer (HNC) cell lines studied and <jats:italic>DOK1<\/jats:italic> CpG hypermethylation correlated with loss of gene expression in these cells. <jats:italic>DOK1<\/jats:italic> expression could be restored <jats:italic>via<\/jats:italic> demethylating treatment using 5\u2010aza\u20102\u2032deoxycytidine. In addition, transduction of cancer cell lines with <jats:italic>DOK1<\/jats:italic> impaired their proliferation, consistent with the critical role of epigenetic silencing of <jats:italic>DOK1<\/jats:italic> in the development and maintenance of malignant cells. We further observed that <jats:italic>DOK1<\/jats:italic> hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitt's lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of <jats:italic>DOK1<\/jats:italic> methylation, suggesting that <jats:italic>DOK1<\/jats:italic> hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of <jats:italic>DOK1<\/jats:italic> gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of <jats:italic>DOK1<\/jats:italic> is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic\u2010based therapy.<\/jats:p>","DOI":"10.1002\/ijc.26299","type":"journal-article","created":{"date-parts":[[2011,7,27]],"date-time":"2011-07-27T15:42:20Z","timestamp":1311781340000},"page":"2484-2494","source":"Crossref","is-referenced-by-count":30,"title":["Inactivation of the putative suppressor gene <i>DOK1<\/i> by promoter hypermethylation in primary human 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