Format

Send to

Choose Destination
Int J Cancer. 2015 Sep 15;137(6):1352-61. doi: 10.1002/ijc.29491. Epub 2015 Mar 13.

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

Author information

1
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Division of Hematology, Department of Internal Medicine, the Ohio State University, Columbus, OH.
3
Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Freiburg, Germany.
4
Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Department of Internal Medicine III, University of Ulm, Germany.
6
Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Medicine V, University of Heidelberg, Heidelberg, Germany.

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.

KEYWORDS:

DNA methylation; IKKβ; NF-κB; epigenetics; miR-708; microRNA

PMID:
25704289
DOI:
10.1002/ijc.29491
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center