Abstract
Kaiso, a member of the BTB/POZ zinc finger protein family, functions as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or to methyl-CpG dinucleotides. Previously, we demonstrated that Kaiso overexpression and nuclear localization correlated with the progression of prostate cancer (PCa). Therefore, our objective was to explore the molecular mechanisms underlying Kaiso-mediated PCa progression. Comparative analysis of miRNA arrays revealed that 13 miRNAs were significantly altered (> 1.5 fold, p < 0.05) in sh-Kaiso PC-3 compared to sh-Scr control cells. Real-time PCR validated that three miRNAs (9, 31, 636) were increased in sh-Kaiso cells similar to cells treated with 5-aza-2′-deoxycytidine. miR-31 expression negatively correlated with Kaiso expression and with methylation of the miR-31 promoter in a panel of PCa cell lines. ChIP assays revealed that Kaiso binds directly to the miR-31 promoter in a methylation-dependent manner. Over-expression of miR-31 decreased cell proliferation, migration and invasiveness of PC-3 cells, whereas cells transfected with anti-miR-31 restored proliferation, migration and invasiveness of sh-Kaiso PC-3 cells. In PCa patients, Kaiso high/miR-31 low expression correlated with worse overall survival relative to each marker individually. In conclusion, these results demonstrate that Kaiso promotes cell migration and invasiveness through regulation of miR-31 expression.
Highlights
prostate cancer (PCa) is the most frequently diagnosed cancer and a leading cause of cancer death, with the mortality and morbidity being mainly due to tumor invasion and metastasis [1]
We demonstrated that Kaiso is responsible for methylation-dependent transcriptional silencing of various genes in both PC-3 and DU- 145 cells that were stably transfected with sh-Kaiso pRFP-C-RS plasmid or control plasmid [16] (Supplementary Figure 1)
Since Kaiso is a transcriptional repressor, we proposed that it regulates the expression of miRNAs, which in turn, repress expression of target genes
Summary
PCa is the most frequently diagnosed cancer and a leading cause of cancer death, with the mortality and morbidity being mainly due to tumor invasion and metastasis [1]. It is necessary to unravel the genetic and epigenetic molecular regulation associated with this transition and to develop a rational approach to treatment. Epigenetic silencing of tumor suppressor genes contributes to the pathogenesis of various cancers, including PCas. DNA methylation, a common epigenetic change, results from changes in cytosine methylation, typically at cytosine-guanine dinucleotides (CpG), or from changes in DNA-associated proteins. DNA methylation, a common epigenetic change, results from changes in cytosine methylation, typically at cytosine-guanine dinucleotides (CpG), or from changes in DNA-associated proteins Like their gene counterparts, microRNAs (miRNAs) are subject to epigenetic regulatory mechanisms such as promoter CpG island hypermethylation and transcriptional deregulation or repression [3, 4]. To date most studies have focused on the genes targeted by miRNA, and the molecular mechanisms that regulate expression of miRNAs are not yet well defined
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