Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers
| Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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| Data(s) |
05/11/2013
05/11/2013
2012
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| Resumo |
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. La Ligue Nationale contre le Cancer (France) La Ligue Nationale contre le Cancer (France) IARC IARC La "Bourse de la Cooperation Francaise'' La Bourse de la Cooperation Francaise La Ligue Regionale de la Lutte Contre le Cancer du Rhone et de la Drome La Ligue Regionale de la Lutte Contre le Cancer du Rhone et de la Drome National Institutes of Health/National Cancer Institute (NIH/NCI) National Institutes of Health/National Cancer Institute (NIH/NCI) [R03 CA122396-02] Association pour la Recherche sur le Cancer (ARC, France) Association pour la Recherche sur le Cancer (ARC, France) la Ligue Nationale Francaise Contre le Cancer la Ligue Nationale Francaise Contre le Cancer The Swiss Bridge Award The Swiss Bridge Award National Institutes of Health/National Cancer Institute (NIH/NCI), USA National Institutes of Health/National Cancer Institute (NIH/NCI), USA [R03 CA122396-02] |
| Identificador |
INTERNATIONAL JOURNAL OF CANCER, MALDEN, v. 130, n. 11, supl. 1, Part 2, pp. 2484-2494, 37043, 2012 0020-7136 http://www.producao.usp.br/handle/BDPI/41264 10.1002/ijc.26299 |
| Idioma(s) |
eng |
| Publicador |
WILEY-BLACKWELL MALDEN |
| Relação |
INTERNATIONAL JOURNAL OF CANCER |
| Direitos |
closedAccess Copyright WILEY-BLACKWELL |
| Palavras-Chave | #DOK1 #DNA HYPERMETHYLATION #GENE SILENCING #TUMOUR SUPPRESSOR #CANCER #CHRONIC LYMPHOCYTIC-LEUKEMIA #ACTIVATED PROTEIN-KINASE #DNA METHYLATION #EXPRESSION #P62(DOK) #PYROSEQUENCING(TM) #PROFILES #MUTATION #CELLS #PCR #ONCOLOGY |
| Tipo |
article original article publishedVersion |
