Immunity drives <i>TET1</i> regulation in cancer through NF-κB

Abstract

Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to <i>TET1</i> regulation. We further demonstrate that <i>TET1</i> repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between <i>TET1</i> expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice, <i>TET1</i> is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the <i>TET1</i> promoter. We lastly show that these findings extend to other cancer types, including melanoma, lung, and thyroid cancers. Together, our data suggest a novel mode of regulation for <i>TET1</i> in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.