Epigenetic silencing of miR-708 enhances NF-κB signaling in chronic lymphocytic leukemia

• Verfasst von: Bär, Constance [VerfasserIn]
• Verfasst von: Oakes, Christopher C. [VerfasserIn]
• Verfasst von: Ruppert, Amy S. [VerfasserIn]
• Verfasst von: Claus, Rainer [VerfasserIn]
• Verfasst von: Kim‐Wanner, Soo-Zin [VerfasserIn]
• Verfasst von: Mertens, Daniel [VerfasserIn]
• Verfasst von: Zenz, Thorsten [VerfasserIn]
• Verfasst von: Stilgenbauer, Stephan [VerfasserIn]
• Verfasst von: Byrd, John C. [VerfasserIn]
• Verfasst von: Plass, Christoph [VerfasserIn]
• Titel: Epigenetic silencing of miR-708 enhances NF-κB signaling in chronic lymphocytic leukemia
• Verf.angabe: 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
• E-Jahr: 2015
• Jahr: 20 February 2015
• Umfang: 11 S.
• Fussnoten: Gesehen am 29.072020
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2015
• Band/Heft Quelle: 137(2015), 6, Seite 1352-1361
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.29491
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: DNA methylation
• Sach-SW: epigenetics
• Sach-SW: IKKβ
• Sach-SW: microRNA
• Sach-SW: miR-708
• Sach-SW: NF-κB
• K10plus-PPN: 1725831600

Abstract

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.