MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1.
Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15(INK4b) and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3' untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3' untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.
Garzon
Ramiro
R
Department of Medicine, Ohio State University, Columbus, 43210, USA.
Liu
Shujun
S
Fabbri
Muller
M
Liu
Zhongfa
Z
Heaphy
Catherine E A
CE
Callegari
Elisa
E
Schwind
Sebastian
S
Pang
Jiuxia
J
Yu
Jianhua
J
Muthusamy
Natarajan
N
Havelange
Violaine
V
Volinia
Stefano
S
Blum
William
W
Rush
Laura J
LJ
Perrotti
Danilo
D
Andreeff
Michael
M
Bloomfield
Clara D
CD
Byrd
John C
JC
Chan
Kenneth
K
Wu
Lai-Chu
LC
Croce
Carlo M
CM
Marcucci
Guido
G
D020413:3' Untranslated Regions / Q000235:genetics; D000208:Acute Disease; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors; D000097584:DNA Methyltransferase 3B
D020413:3' Untranslated Regions; D050762:Cyclin-Dependent Kinase Inhibitor p15; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D016329:Sp1 Transcription Factor; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C506487:ESR1 protein, human; C000619380:DNMT1 protein, human