MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B

Abstract

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-cell lung cancer. Here we show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lung cancer cell lines restores normal patterns of DNA methylation, induces reexpression of methylation-silenced tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer. epigenetics ͉ tumor-suppressor genes

MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

“…Consistently, miR-29b regulates Mcl-1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in cholangiocarcinoma cells, and controls Tcl-1 in chronic lymphatic leukemia cells (Pekarsky et al, 2006;Mott et al, 2007). The miR-29 family members also target DNMT3A and DNMT3B, and can thereby restore patterns of DNA methylation and expression of silenced tumor suppressor genes (Fabbri et al, 2007). Although we did not exclude the possibility that inhibition of Src or manipulation of miR-29b changed methylation of the ID1 promoter in our study, we demonstrated that miR-29b binds to the ID1 3 0 -UTR, and that this direct interaction has functional implications.…”

“…As miR-29b is known to target DNA methyltransferase (DNMT)-3A and -3B in lung cancer (Fabbri et al, 2007), we measured DNMT-3B expression as a control for the effectiveness of miR-29b inhibition. Anti-miR29b led to a two-to threefold increase of DNMT-3B mRNA and protein levels in A549 and H460 cells ( Figure 4b and Supplementary Figure 2a).…”

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

“…This miR has been shown to inhibit tumorigenic growth by reducing expression of DNA methyl transferase (DNMT) (Fabbri et al, 2007). Paradoxically, LMP1 has been shown to …”

MicroRNA-148a Can Regulate Runt-Related Transcription Factor 3 Gene Expression via Modulation of DNA Methyltransferase 1 in Gastric Cancer

“…There are recent reports that specific miRNAs participate in human cancers by regulating DNA methylation via DNMTs, resulting in the silence or promotion of methylationsensitive tumor suppressor genes. For example, Fabbri et al (2007) demonstrated that an increase in miR-29 expression in non-small-cell lung carcinoma cell lines inversely correlated with DNMT3A and DNMT3B levels. In addition, DNA methylation and methylation-silenced tumor suppressor gene expression (fragile histidine triad [FHIT] and WW domain-containing oxidoreductase [WWOX]) were restored to normal, and tumorigenicity was inhibited in vitro and in vivo.…”