Aberrant regulation of miRNAs and epigenetic abnormalities often occur in cancer. Two new studies show that miR-22 is an epigenetic modifier that promotes stemness and metastasis in cancer by targeting an enzyme that regulates DNA demethylation (Cell 154, 1–14; Cell Stem Cell 13, 87–101).

Su Jung Song et al. found that miR-22 was highly expressed in individuals with myelodysplastic syndrome and high-grade tumors, and that this correlated with poor survival. In mice, expression of miR-22 in the hematopoietic compartment increased stem cell maintenance and self-renewal, and this boost in hematopoiesis eventually caused hematological malignancy. Expression of the miRNA in mouse mammary glands promoted stemness, epithelial to mesenchymal transition and breast tumor development, as well as metastatic growth in a mouse model in which breast tumors spontaneously metastasize to the lung.

In both models, miR-22 blocked expression of TET family members, which induce DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine. TET mutations are often found in human leukemias, and lack of Tet2 results in malignant transformation in mice; the two new studies suggest that regulation of TET2 by miR-22 may be also a key tumorigenic pathway in the hematological compartment. In breast tissue, miR-22 also promoted malignancy by suppressing the expression of TET2 and TET3. Moreover, miR-22 overexpression triggered metastasis through epigenetically silencing expression of the antimetastatic miR-200 family by targeting TET family members. The authors validated this link between miR-22 and the TET–miR-200 axis in human breast samples.

These findings emphasize the importance of antagonistic miRNA interactions and their influences on global epigenetic modifiers, which can result in tumor progression and metastasis, and also identify an oncogenic miR that acts in several tissues. Further work will be required to assess the therapeutic potential of targeting miR-22 to avert metastasis.