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Immunity drives TET1 regulation in cancer through NF-κB

Evelyne Collignon1, Annalisa Canale2, Clémence Al Wardi1

  • 1Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB (Université libre de Bruxelles)-Cancer Research Center (U-CRC), ULB, Brussels, Belgium.

Science Advances
|June 26, 2018
PubMed

Insights

Ten-eleven translocation (TET) enzymes are crucial for DNA demethylation and gene regulation but are often down-regulated in cancer. This study reveals that the nuclear factor κB (NF-κB) pathway represses TET1 in breast cancer, impacting immune responses.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Immunology

Background:

  • Ten-eleven translocation (TET) enzymes (TET1, TET2, TET3) regulate gene expression via DNA demethylation, converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).
  • TET enzyme down-regulation is a common event in various cancers, suggesting a role in tumorigenesis.
  • Basal-like breast cancer (BLBC) is an aggressive subtype with distinct molecular features.

Purpose of the Study:

  • To investigate the role of TET1 in basal-like breast cancer (BLBC).
  • To explore the relationship between TET1 expression, immune markers, and immune cell infiltration in BLBC.
  • To elucidate the regulatory mechanisms controlling TET1 expression in cancer, particularly the involvement of the nuclear factor κB (NF-κB) pathway.

Main Methods:

  • Genome-wide analysis of 5-hydroxymethylcytosine (5hmC) modifications in BLBC.
  • Correlation analysis between TET1 expression and immune markers/cell infiltration.
  • In vitro and in vivo studies using breast cancer cell lines and mouse models.
  • Chromatin immunoprecipitation (ChIP) to assess p65 binding to the TET1 promoter.

Main Results:

  • Genome-wide 5hmC changes were observed in BLBC, linked to TET1 regulation.
  • TET1 repression was associated with increased expression of immune markers and higher immune cell infiltration.
  • An inverse correlation was found between TET1 expression and nuclear factor κB (NF-κB) activity in BLBC tissues.
  • NF-κB activation, via p65 binding to the TET1 promoter, led to TET1 down-regulation in breast cancer cells (in vitro and in mice).
  • These regulatory patterns were also observed in melanoma, lung, and thyroid cancers.

Conclusions:

  • The study identifies a novel mechanism of TET1 regulation in cancer, driven by the NF-κB pathway.
  • NF-κB-mediated repression of TET1 influences the tumor immune microenvironment.
  • This work highlights a new paradigm where immune signaling pathways can epigenetically modulate cancer cells.

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