Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer.
Recently, we and others identified the microRNA miR-34a as a target of the tumor suppressor gene product p53. Ectopic miR-34a induces a G(1) cell cycle arrest, senescence and apoptosis. Here we report that miR-34a expression is silenced in several types of cancer due to aberrant CpG methylation of its promoter. 19 out of 24 (79.1%) primary prostate carcinomas displayed CpG methylation of the miR-34a promoter and concomitant loss of miR-34a expression. CpG methylation of the miR-34a promoter was also detected in breast (6/24; 25%), lung (7/24; 29.1%), colon (3/23; 13%), kidney (3/14; 21.4%), bladder (2/6; 33.3%) and pancreatic (3/19; 15.7%) carcinoma cell lines, as well as in melanoma cell lines (19/44; 43.2%) and primary melanoma (20/32 samples; 62.5%). Silencing of miR-34a was dominant over its transactivation by p53 after DNA damage. Re-expression of miR-34a in prostate and pancreas carcinoma cell lines induced senescence and cell cycle arrest at least in part by targeting CDK6. These results show that miR-34a represents a tumor suppressor gene which is inactivated by CpG methylation and subsequent transcriptional silencing in a broad range of tumors.
Lodygin
Dmitri
D
Molecular Oncology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Tarasov
Valery
V
Epanchintsev
Alexey
A
Berking
Carola
C
Knyazeva
Tatjana
T
Körner
Henrike
H
Knyazev
Piotr
P
Diebold
Joachim
J
Hermeking
Heiko
H
D000818:Animals; D045744:Cell Line, Tumor; D018899:CpG Islands; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D051361:Cyclin-Dependent Kinase 6