Epigenetic silencing of miR-708 enhances NF-κB signaling in chronic lymphocytic leukemia
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and their deregulation is involved in tumor development. Epigenetic gene silencing in cancer by DNA methylation contributes to the silencing of tumor-suppressor genes, including miRNAs. We have recently shown that the promoter...
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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
20 February 2015
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| In: |
International journal of cancer
Year: 2015, Jahrgang: 137, Heft: 6, Pages: 1352-1361 |
| ISSN: | 1097-0215 |
| DOI: | 10.1002/ijc.29491 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/ijc.29491 Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.29491 
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| Verfasserangaben: | Constance Baer, Christopher C. Oakes, Amy S. Ruppert, Rainer Claus, Soo-Zin Kim‐Wanner, Daniel Mertens, Thorsten Zenz, Stephan Stilgenbauer, John C. Byrd and Christoph Plass |
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| 520 | |a MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and their deregulation is involved in tumor development. Epigenetic gene silencing in cancer by DNA methylation contributes to the silencing of tumor-suppressor genes, including miRNAs. We have recently shown that the promoter of miR-708 is aberrantly methylated in chronic lymphocytic leukemia (CLL). To characterize the molecular signaling networks that are influenced by miR-708, we performed a luciferase-based screen evaluating the effects of ectopic miR-708 expression on leukemia-relevant signaling pathways. We found that miR-708 strongly repressed NF-κB signaling, a pathway known to be deregulated in CLL. Among the predicted miR-708 targets was IKKβ (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase-β/IKBKB), a key kinase facilitating NF-κB signaling. We validated the interaction of miR-708 with the 3′-untranslated region of IKKβ and found that miR-708 overexpression represses endogenous IKKβ. Phosphorylation of the IKKβ target IκBα and expression of known NF-κB target genes were impaired by miR-708. Furthermore, we identified an enhancer region downstream of the miR-708 promoter that displays a distinct DNA methylation status in CLL. High enhancer methylation is significantly correlated with lower miR-708 expression and is predominantly found in patients with poor prognosis and shorter time to treatment. These results demonstrate that miR-708 regulates the NF-κB pathway by targeting IKKβ, and that methylation of a key enhancer region contributes to its suppression in CLL. | ||
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