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

Author

Listed:
  • Ken-ichi Takayama

    (Graduate School of Medicine, The University of Tokyo
    Graduate School of Medicine, The University of Tokyo)

  • Aya Misawa

    (Graduate School of Medicine, The University of Tokyo)

  • Takashi Suzuki

    (Graduate School of Medicine, Tohoku University)

  • Kiyoshi Takagi

    (Graduate School of Medicine, Tohoku University)

  • Yoshihide Hayashizaki

    (RIKEN Omics Science Center (OSC), RIKEN Yokohama Institute
    RIKEN Preventive Medicine & Diagnosis Innovation Program)

  • Tetsuya Fujimura

    (Graduate School of Medicine, The University of Tokyo)

  • Yukio Homma

    (Graduate School of Medicine, The University of Tokyo)

  • Satoru Takahashi

    (Nihon University School of Medicine)

  • Tomohiko Urano

    (Graduate School of Medicine, The University of Tokyo
    Graduate School of Medicine, The University of Tokyo)

  • Satoshi Inoue

    (Graduate School of Medicine, The University of Tokyo
    Graduate School of Medicine, The University of Tokyo
    Research Center for Genomic Medicine, Saitama Medical University)

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.

Suggested Citation

  • Ken-ichi Takayama & Aya Misawa & Takashi Suzuki & Kiyoshi Takagi & Yoshihide Hayashizaki & Tetsuya Fujimura & Yukio Homma & Satoru Takahashi & Tomohiko Urano & Satoshi Inoue, 2015. "TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9219
    DOI: 10.1038/ncomms9219
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    Cited by:

    1. Jeroen Kneppers & Tesa M. Severson & Joseph C. Siefert & Pieter Schol & Stacey E. P. Joosten & Ivan Pak Lok Yu & Chia-Chi Flora Huang & Tunç Morova & Umut Berkay Altıntaş & Claudia Giambartolomei & Ji, 2022. "Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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