Abstract
Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antimetabolites, Antineoplastic / pharmacology
-
Azacitidine / pharmacology
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism
-
Biomimetics*
-
Blotting, Western
-
Bone Marrow / metabolism
-
Bone Marrow / pathology
-
Case-Control Studies
-
Cell Cycle
-
Cell Proliferation
-
Cellular Microenvironment / drug effects
-
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
-
DNA (Cytosine-5-)-Methyltransferases / genetics*
-
DNA (Cytosine-5-)-Methyltransferases / metabolism
-
DNA Methylation*
-
DNA Methyltransferase 3A
-
DNA Methyltransferase 3B
-
Gene Expression Profiling
-
Humans
-
Immunoenzyme Techniques
-
Leukemia, Plasma Cell / genetics
-
Leukemia, Plasma Cell / pathology
-
Leukemia, Plasma Cell / prevention & control*
-
Male
-
Mice
-
Mice, SCID
-
MicroRNAs / chemical synthesis
-
MicroRNAs / genetics*
-
Multiple Myeloma / genetics
-
Multiple Myeloma / pathology
-
Multiple Myeloma / prevention & control*
-
Oligonucleotide Array Sequence Analysis
-
RNA, Messenger / genetics
-
RNA, Small Interfering / genetics
-
Real-Time Polymerase Chain Reaction
-
Reverse Transcriptase Polymerase Chain Reaction
-
Tumor Cells, Cultured
Substances
-
Antimetabolites, Antineoplastic
-
Biomarkers, Tumor
-
DNMT3A protein, human
-
Dnmt3a protein, mouse
-
MIRN29a microRNA, human
-
MicroRNAs
-
RNA, Messenger
-
RNA, Small Interfering
-
DNA (Cytosine-5-)-Methyltransferases
-
DNA Methyltransferase 3A
-
Azacitidine