title: 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.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Saulnier
authors.forename: Thomas
authors.initials: T
authors.lastname: Vaissière
authors.forename: Jiping
authors.initials: J
authors.lastname: Yue
authors.forename: Maha
authors.initials: M
authors.lastname: Siouda
authors.forename: Marine
authors.initials: M
authors.lastname: Malfroy
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.forename: Marion
authors.initials: M
authors.lastname: Creveaux
authors.forename: Sinto
authors.initials: S
authors.lastname: Sebastian
authors.forename: Naveed
authors.initials: N
authors.lastname: Shahzad
authors.forename: Tarik
authors.initials: T
authors.lastname: Gheit
authors.forename: Ishraq
authors.initials: I
authors.lastname: Hussain
authors.forename: Mariela
authors.initials: M
authors.lastname: Torrente
authors.forename: Fausto Antonio
authors.initials: FA
authors.lastname: Maffini
authors.forename: Luca
authors.initials: L
authors.lastname: Calabrese
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiesa
authors.forename: Cyrille
authors.initials: C
authors.lastname: Cuenin
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.forename: Ikbal
authors.initials: I
authors.lastname: Fathallah
authors.forename: Elena
authors.initials: E
authors.lastname: Matos
authors.forename: Alexander
authors.initials: A
authors.lastname: Daudt
authors.forename: Sergio
authors.initials: S
authors.lastname: Koifman
authors.forename: Victor
authors.initials: V
authors.lastname: Wünsch-Filho
authors.forename: Ana M B
authors.initials: AM
authors.lastname: Menezes
authors.forename: Maria-Paula
authors.initials: MP
authors.lastname: Curado
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077209:Decitabine; D005260:Female; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D010750:Phosphoproteins; C411762:RASSF1 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine