TET1 Suppresses Cancer Invasion by Activating the Tissue Inhibitors of Metalloproteinases

SummaryTumor suppressor gene silencing through cytosine methylation contributes to cancer formation. Whether DNA demethylation enzymes counteract this oncogenic effect is unknown. Here, we show that TET1, a dioxygenase involved in cytosine demethylation, is downregulated in prostate and breast cancer tissues. TET1 depletion facilitates cell invasion, tumor growth, and cancer metastasis in prostate xenograft models and correlates with poor survival rates in breast cancer patients. Consistently, enforced expression of TET1 reduces cell invasion and breast xenograft tumor formation. Mechanistically, TET1 suppresses cell invasion through its dioxygenase and DNA binding activities. Furthermore, TET1 maintains the expression of tissue inhibitors of metalloproteinase (TIMP) family proteins 2 and 3 by inhibiting their DNA methylation. Concurrent low expression of TET1 and TIMP2 or TIMP3 correlates with advanced node status in clinical samples. Together, these results illustrate a mechanism by which TET1 suppresses tumor development and invasion partly through downregulation of critical gene methylation.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► TET1 depletion facilitates cancer invasion and correlates with poor survival in breast cancer patients
► TET1 dioxygenase and DNA binding activity is required for invasion suppression
► TET1 suppresses invasion partly through TIMP activation and MMP inhibition