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Sci Adv. 2018 Jun 20;4(6):eaap7309. doi: 10.1126/sciadv.aap7309. eCollection 2018 Jun.

Immunity drives TET1 regulation in cancer through NF-κB.

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Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)-Cancer Research Center (U-CRC), ULB, Brussels, Belgium.
Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Cancer, University of Liège, Liège, Belgium.
Molecular Immunology Unit, Institut Jules Bordet, ULB, Brussels, Belgium.
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
Service of Molecular Virology, Department of Molecular Biology, U-CRC, ULB, Gosselies, Belgium.
Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
Breast Cancer Translational Research Laboratory, Jules Bordet Institute, ULB, Brussels, Belgium.


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 TET1 regulation. We further demonstrate that TET1 repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between TET1 expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice, TET1 is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the TET1 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 TET1 in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.

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