Abstract
Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3′UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.
Highlights
The majority of oncogenic signaling pathways converge on sets of transcription factors (TFs) that control gene expression patterns involved in tumor formation and progression.[1]
Among such transcriptome modifiers there are microRNAs, small non-coding RNAs (20–22 nucleotides in length) that play an important role in regulation of gene expression, virtually affecting all cellular processes such as differentiation, proliferation, survival and apoptosis.[9,10]
Genetic disorders and complex diseases have been found to be associated with perturbations of the intertwined regulatory network between TFs and miRNAs.[11]
Summary
The majority of oncogenic signaling pathways converge on sets of transcription factors (TFs) that control gene expression patterns involved in tumor formation and progression.[1]. Expression of TFs is modulated by a number of genomic and epigenomic changes as well as various transcriptome modifiers Among such transcriptome modifiers there are microRNAs (miRNAs), small non-coding RNAs (20–22 nucleotides in length) that play an important role in regulation of gene expression, virtually affecting all cellular processes such as differentiation, proliferation, survival and apoptosis.[9,10] Genetic disorders and complex diseases have been found to be associated with perturbations of the intertwined regulatory network between TFs and miRNAs.[11] TFs and miRNAs frequently form feed-forward loops to regulate transcription of functionally critical genes.[12]. We have identified miR-23b as a negative regulator of Sp1 expression and provided evidence of the tumor suppressor role of miR-23b, and its downregulation as a consequence of epigenetic mechanisms, supporting the existence of a novel feed-forward loop with a critical growth and survival role in MM and WM
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