Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers.
Many distinct regions of 3p show frequent allelic losses in a wide range of tumour types. Previously, the BLU candidate tumour suppressor gene (TSG) encoded by a gene-rich critical deleted region in 3p21.3 was found to be inactivated rarely in lung cancer, although expression was downregulated in a subset of lung tumour cell lines. To elucidate the role of BLU in tumorigenesis, we analysed BLU promoter methylation status in tumour cell lines and detected promoter region hypermethylation in 39% lung, 42% breast, 50% kidney, 86% neuroblastoma and 80% nasopharyngeal (NPC) tumour cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumour cell lines. Expression was recovered in tumour cell lines treated with 5-aza 2-deoxycytidine. Exogenous expression of BLU in neuroblastoma (SK-N-SH) and NSCLC (NCI-H1299) resulted in reduced colony formation efficiency, in vitro. Furthermore, methylation of the BLU promoter region was detected in primary sporadic SCLC (14%), NSCLC (19%) and neuroblastoma (41%). As frequent methylation of the RASSF1A 3p21.3 TSG has also been reported in these tumour types, we investigated whether BLU and RASSF1A methylation were independent or related events. No correlation was found between hypermethylation of RASSF1A and BLU promoter region CpG islands in SCLC or neuroblastoma. However, there was association between RASSF1A and BLU methylation in NSCLC (P=0.0031). Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of BLU in the pathogenesis of common human cancers and that methylation inactivation of BLU occurs independent of RASSF1A in SCLC and neuroblastoma tumours.
Agathanggelou
Angelo
A
Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, university of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK.
Dallol
Ashraf
A
Zöchbauer-Müller
Sabine
S
Morrissey
Catherine
C
Honorio
Sofia
S
Hesson
Luke
L
Martinsson
Tommy
T
Fong
Kwun M
KM
Kuo
Michael J
MJ
Yuen
Po Wing
PW
Maher
Eamonn R
ER
Minna
John D
JD
Latif
Farida
F
D001483:Base Sequence; D018288:Carcinoma, Small Cell / Q000235:genetics; D002893:Chromosomes, Human, Pair 3; D018899:CpG Islands; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human