DNA methylation controls metastasis-suppressive 14q32-encoded miRNAs

Expression of 14q32-encoded miRNA is a favorable prognostic factor in patients with metastatic cancer. In this study, we use 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 miRNA 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 miRNA, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells. Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNA and resistance to 5-Aza-dC-induced suppression of AIM. Expression of methylation-dependent 14q32 miRNA 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 miRNA.

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