miR-29s: a family of epi-miRNAs with therapeutic implications in hematologic malignancies

Abstract

A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies.

Keywords: hematologic malignancies; miR-29a; miR-29b; miR-29c; multiple myeloma.

Figure 1

Cartoon showing the most relevant transcription factors and co-factors that inhibit miR-29 a/b-1 (A) or miR-29b-2/c (B) expression.

Figure 2

Down-modulation of miR-29b by epigenetic feedback loops sustaining proliferation and survival of (A) Multiple Myeloma, (B) AML and (C) B-cell lymphoma cells. A. In MM cells, SP1 acts by repressing miR-29b promoter thus reducing miR-29b expression; miR-29b in turn targets SP1, DNMT3A and DNMT3B, thus inducing global DNA hypomethylation and reactivation of SOCS-1 by promoter hypomethylation. B. In AML cells, a molecular complex formed by HDAC1-3/NF-kB and SP1 represses miR-29b promoter transcription. In turn, miR-29b targets SP1, a DNMT-1 transactivator, DNMT3A and DNMT3B, thus up-regulating ESR1 and p15 by promoter hypomethylation. C. In aggressive B-cell lymphomas, repression of miR-29b is accomplished by a multimeric complex comprising c-MYC, HDAC3, SUZ12 and EZH2 which represses miR-29b promoter. Of note, EZH2 causes H3K27me3-dependent repression of miR-494, thus up-regulating the miR-494 target c-MYC, which in turn promotes EZH2 expression by inhibiting miR-26. miR-29b-dependent anti-proliferative effects in B-cell lymphomas rely on CDK6 and IGF1R targeting.