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

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

Author information

1
Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
2
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
3
Department of Pathology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.
4
RIKEN Omics Science Center (OSC), RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045, Japan.
5
RIKEN Preventive Medicine &Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.
6
Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
7
Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-0032, Japan.
8
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.

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.

PMID:
26404510
DOI:
10.1038/ncomms9219
[Indexed for MEDLINE]

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