Abstract
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer. In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-2'-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster. DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-DMR), which acts as a cis-regulatory element for 14q32 miRNA expression. 5-Aza-dC activated demethylation of the MEG3-DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver metastasis and correlated with improved clinical outcomes in patients with metastatic cancer. These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs. SIGNIFICANCE: This study investigates epigenetic regulation of metastasis-suppressive miRNAs and the effect on metastasis.
Highlights
MiRNAs play a pivotal role in the regulation of metastasis [1,2,3]
By comparing whole-genome miRNA expression in wild-type (WT) and DNMT1/DNMT3BÀ/À double knockout (DKO) HCT116 cells, we identified two miRNA clusters overexpressed in DKO cells, which mapped to the 14q32 and 19q13 genomic loci (Fig. 1A and B; Supplementary Table S3; refs. 18, 27)
We examined the association between miRNA expression and overall survival in patients treated by hepatic resection of limited colorectal liver metastases at the University of Chicago (Chicago, IL) and NorthShore Hospital
Summary
In the context of clinical outcomes, patients with limited numbers and slow progression of metastases, termed oligometastases, exhibit unique patterns of differentially expressed miRNAs in contrast to patients with widely disseminated or rapidly progressive metastatic disease [4, 5]. These miRNAs are designated "oligomiRs" to recognize their association with oligometastases [6]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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