Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers.

Abstract

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2'deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 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 DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.

• Authors: Amandine Saulnier, Thomas Vaissière, Jiping Yue, Maha Siouda, Marine Malfroy, Rosita Accardi, Marion Creveaux, Sinto Sebastian, Naveed Shahzad, Tarik Gheit, Ishraq Hussain, Mariela Torrente, Fausto Antonio Maffini, Luca Calabrese, Fausto Chiesa, Cyrille Cuenin, Ruchi Shukla, Ikbal Fathallah, Elena Matos, Alexander Daudt, Sergio Koifman, Victor Wünsch-Filho, Ana M B Menezes, Maria-Paula Curado, David Zaridze, Paolo Boffetta, Paul Brennan, Massimo Tommasino, Zdenko Herceg, Bakary S Sylla
• Journal: International journal of cancer (Int J Cancer) Vol. 130 Issue 11 Pg. 2484-94 (Jun 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21796618 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• DNA-Binding Proteins
• DOK1 protein, human
• Phosphoproteins
• RASSF1 protein, human
• RNA-Binding Proteins
• Tumor Suppressor Proteins
• Decitabine
• Azacitidine

Topics

• Adult
• Aged
• Azacitidine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• DNA Methylation
• DNA-Binding Proteins (antagonists & inhibitors, genetics)
• Decitabine
• Female
• Genes, Tumor Suppressor
• Head and Neck Neoplasms (genetics, pathology)
• Humans
• Male
• Middle Aged
• Phosphoproteins (antagonists & inhibitors, genetics)
• Promoter Regions, Genetic
• RNA-Binding Proteins (antagonists & inhibitors, genetics)
• Risk Factors
• Tumor Suppressor Proteins (genetics)