Lysine demethylase KDM2A promotes cancer progression in triple-negative breast cancer by inhibiting TET2

[[abstract]]The coupling between DNA methylation and histone modification contributes to aberrant expression of genes associated with tumor development. Our previous study demonstrated that lysine demethylase 2A (KDM2A) functions as an oncogene in breast cancer by promoting cancer stemness and angiogenesis via up-regulation of Jagged1 to activate the Notch signaling. Here, we found that knockdown of KDM2A significantly increases the 5-hydroxymethylcytosine (5'-hmc) level in genomic DNA and expression of tet-eleven translocation 2 (TET2) in various triple-negative breast cancer cell lines. Ectopic expression of KDM2A inhibits TET2 expression in KDM2A-depleted cells suggesting TET2 is a transcriptional repression target of KDM2A. Up-regulation of TET2 in the KDM2A-depleted cells induces the re-activation of two TET downstream genes epithelial cell adhesion molecule (EpCAM) and E-cadherin which leads to the inhibition of migration and invasion. Take together, we demonstrate for the first time that TET2 is a direct repression target of KDM2A and reveal a novel mechanism by which KDM2A promotes DNA methylation and breast cancer progression via the inhibition of a DNA demethylase