The first reported mirna cluster was mir-15a and mir-16-1 and these show altered expressions in the cancer cells
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The deregulation of microRNA (miRNA) has been frequently identified in a variety of tumors and has been linked to tumorigenesis. However, the underlying mechanism responsible has been challenging to ascertain and has not been well elucidated. Cluster 15a/16-1 miRNAs (miR-15a/16-1), located at 13q14.3, were the first demonstrated tumor suppressor miRNA gene (Calin et al., 2002). Expression of these miRNAs inhibits the cell proliferation, promotes apoptosis of cancer cells and suppresses tumorigenicity by targeting multiple oncogenes (Aqeilan et al., 2010). Loss or downregulation of these miRNAs has been reported in a variety of hematopoietic and solid tumors (Calin et al., 2002; Bottoni et al., 2005; Bonci et al., 2008; Bandi et al., 2009; Davidson-Moncada et al., 2010). Our recent study demonstrated that miR-15a/16-1 is downregulated in the majority of patients with mantle cell lymphoma (MCL) (Zhao et al., 2010). However, the mechanism responsible for miR-15a/16-1 suppression is unknown.
c-Myc (hereafter Myc) is an oncogenic transcription factor that promotes tumorigenesis by activating and repressing its target genes that control the cell growth and proliferation (Meyer and Penn, 2008). Besides direct regulation of the target genes involved in the proliferation and growth, Myc has been recently implicated in controlling the complex networks of miRNAs (O'Donnell et al., 2005; Chang et al., 2008). Myc was reported to suppress the expression of a host of miRNAs in B-cell lymphomas. Among these repressed miRNAs are several putative tumor suppressors, such as the miR-15a/16-1, miR-34a and let-7 family members (Chang et al., 2008; Sotillo et al., 2011). Although the mechanisms by which Myc activates transcription have been extensively studied, less is known about how Myc represses transcription of the target genes as well as miRNAs. It was recently reported that Myc induced transcriptional repression of the target genes Id2 and Gadd153, by recruitment of histone deacetylase 3 (HDAC3) (Kurland and Tansey, 2008). Moreover, N-Myc had been demonstrated to act as a transrepressor by recruiting HDAC1 and HDAC2 (Liu et al., 2007; Marshall et al., 2010). These findings define a novel mechanism of miRNA transcriptional repression by Myc and shed light on the poorly understood mechanism for wide and general miRNA suppression in B-cell lymphomas.