TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

Nat Commun. 2015 Sep 25;6:8219. doi: 10.1038/ncomms9219.

Abstract

Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Aged
  • Androgens / metabolism*
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Humans
  • Hydroxylation
  • Immunohistochemistry
  • Male
  • Mice, Inbred BALB C
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Transplantation
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / metabolism*
  • Receptors, Androgen / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Androgens
  • DNA-Binding Proteins
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • MIRN29a microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Androgen
  • TET2 protein, human
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • TOR Serine-Threonine Kinases

Associated data

  • GEO/GSE58309
  • GEO/GSE58428
  • GEO/GSE62492
  • GEO/GSE66039