ReviewmiRNAs and cancer: An epigenetics view
Introduction
Non-protein-coding RNAs are emerging as a new class of regulatory genes with critical relevance in all cellular processes. microRNAs (miRNAs) are small, single-stranded, non-coding RNAs (19–25 nucleotides in length) that are generated from hairpin transcripts (Ambros, 2004, Kim, 2005). miRNA genes are usually transcribed by RNA polymerase II, similarly to most genes in the genome, generating long primary transcripts (pri-miRNAs; Fig. 1). These primary transcripts are processed by Drosha (a RNAse type III) complexes containing the co-factor Di George syndrome critical region 8 (DGCR8) giving rise to 70–100 nt long pre-miRNAs. An alternative, Drosha-independent, pathway that depends on the splicing machinery has also been described in several species (Yang and Lai, 2011). pre-miRNAs are then processed by the RNAse III Dicer to generate a double-stranded (ds)RNA approximately 22 nt long. This dsRNA includes the mature miRNA (also known as miRNA-5p; in red in Fig. 1) and the complementary strand known as miRNA∗ or miRNA-3p. miRNAs∗ are normally subjected to degradation although they may also act as functional microRNAs. The mature single-stranded microRNA is then able to modulate the expression of target protein-coding mRNAs by base-pairing to partially complementary regions frequently located at the 3′-untranslated regions (3′-UTR) of the target transcript (Fig. 1). The mature miRNA recognizes specific sequences in the mRNAs and recruits Argonaute (Ago) proteins as well as other additional factors such as the trans-activator RNA binding protein (TRBP) in a complex known as RISC (RNA-induced silencing complex). RISC is responsible for site-specific cleavage of the mRNA, enhanced mRNA degradation and repression of its translation (Ambros, 2004, Kim, 2005, Yang and Lai, 2011). Recent evidences suggest that miRNAs can also act on transcripts in a RISC-independent manner (Eiring et al., 2010).
More than a thousand miRNAs exist in the human genome and they are able to modulate the expression of 30–60% of the protein coding genes. In addition, most transcripts can be modulated by multiple miRNAs. Through this regulation, miRNAs play critical roles in development, differentiation, cell proliferation, apoptosis and stress responses. Not surprisingly, these small non-coding RNAs are also implicated in tumor development by regulating the cellular levels of specific oncogenes or tumor suppressor genes (Iorio and Croce, 2012, Lee and Dutta, 2009). The expression of miRNAs is altered in tumor cells by genetic or epigenetic mechanisms or by aberrant expression of transcription factors. In addition, the activity of some miRNAs can also modulate the epigenetic regulation of multiple genes by controlling the levels of DNA methyltransferases or histone deacetylases, among other epigenetic regulators (Iorio and Croce, 2012, Iorio et al., 2010, Kunej et al., 2011, Sato et al., 2011). Finally, recent evidences suggest that miRNAs are able to bind complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression (Fig. 1). The relevant role of miRNAs in tumor development has prompted the search and evaluation of therapeutic strategies targeting these small sequences for cancer therapy (Garofalo and Croce, 2011, Garzon et al., 2010, Iorio and Croce, 2012, Trang et al., 2008).
Section snippets
miRNAs and tumor development
miRNAs were initially discovered in 1993 when a small RNA (lin-4) was associated to the development of the nematode Caenorhabditis elegans (Lee et al., 1993). Several small regulatory RNAs were identified in plants and animals and designated “microRNAs” in 2001 (Lagos-Quintana et al., 2001, Lau et al., 2001, Lee and Ambros, 2001). These pioneer studies suggested that these small sequences could modulate the expression of critical genes involved in development. Their role in human cancer was not
Epigenetic alteration of miRNAs in cancer
Epigenetic regulation generally falls into two categories: DNA methylation and histone modifications. Both types of regulation cooperate tightly and histone deacetylases (HDACs) frequently associate with DNA methyltransferases and with methyl CpG-binding domain proteins (MBDs). In many cases, both modifications work together and effective transcriptional reactivation of certain genes cannot be achieved unless both DNA methylation and HDAC-dependent inhibition are eliminated. Epigenetic
Epigenetic functions of miRNAs
miRNAs are not only modulated by epigenetic regulation as described in the previous section. It is now clear that miRNAs also have specific epigenetic functions. First, a subset of miRNAs controls the expression of important epigenetic regulators, including DNA methyltransferases, HDACs and polycomb group genes. The expression of these miRNAs, known as epi-miRNAs, has therefore important consequences in the epigenetic regulation of multiple cellular pathways and processes. Second, recent
Conclusions
An increasing number of miRNAs are regulated epigenetically and, in parallel, multiple miRNAs are able to modulate the protein levels of epigenetic regulators such as DNA methyltransferases, HDACs or components of the polycomb repressor complexes. In addition, the possibility that miRNAs can directly determine epigenetic modifications in promoter regions suggests that the mechanisms of epigenetic and miRNA regulation are not entirely separable, and they cooperate to establish the gene
Acknowledgements
Malumbres’ lab is funded by grants from the Association for International Cancer Research (AICR #08-0188), Foundation Ramón Areces, the Spanish Ministerio de Economía y Competitividad (MINECO, SAF2009-07973), the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, the OncoBIO Consolider-Ingenio 2010 Programme (CSD2007-00017) from the MINECO, and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).
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