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

Ken Ichi Takayama, Aya Misawa, Takashi Suzuki, Kiyoshi Takagi, Yoshihide Hayashizaki, Tetsuya Fujimura, Yukio Homma, Satoru Takahashi, Tomohiko Urano, Satoshi Inoue

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

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.

Original languageEnglish
Article number8219
JournalNature communications
Volume6
DOIs
Publication statusPublished - 2015 Sep 25
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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