Abstract
MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases.The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Krüppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.
Highlights
Non-coding RNAs including microRNAs have emerged as key regulators of development and disease [1]
To narrow down the main potential regulator(s) of miR-182 cluster expression, we integrated messenger RNAs (mRNAs) microarray expression data for the 46 transcription factors (TFs) with miR-182 levels measured by qPCR in a panel of melanoma cell lines without amplification of the 7q32 locus
Eight candidate genes (KLF4, KLF10, ZEB1, ZNF83, ZNF148, CEBP, BACH1 and PAX9) were selected for further analysis based on their higher expression levels in melanoma compared to normal melanocytes, and individually tested as potential trans-activators of the minimal miR-182 cluster promoter in HEK293T cells
Summary
Non-coding RNAs including microRNAs (miRNAs) have emerged as key regulators of development and disease [1]. MiRNAs are a class of small non-coding RNAs that interfere with the translation and stability of coding messenger RNAs (mRNAs) in a sequence-specific manner [2]. MicroRNA genes are distributed along the genome and can be intergenic, intronic (mirtrons), or exonic (in exons of coding or non-coding genes). They are found as single genes or organized in clusters, i.e, miRNAs located in the same genomic region, usually in less than 10Kb, and transcribed as a single transcriptional unit [4]
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