TY - JOUR
T1 - TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression
AU - Takayama, Ken Ichi
AU - Misawa, Aya
AU - Suzuki, Takashi
AU - Takagi, Kiyoshi
AU - Hayashizaki, Yoshihide
AU - Fujimura, Tetsuya
AU - Homma, Yukio
AU - Takahashi, Satoru
AU - Urano, Tomohiko
AU - Inoue, Satoshi
N1 - Funding Information:
We thank RIKEN for sequencing our samples and National Institute of Genetics (NIG) for analysing sequence data. We thank Dr Hiroyuki Mano (The University of Tokyo) for the bioinformatics analysis of short RNA sequence data. We also thank E. Sakamoto, T. Oishi, K. Kodama and N. Sasaki for technical assistance (establishment of cell lines, cell proliferation assay, cell culture, xenografts, bioinformatics analysis and microarray). This work was supported by Grants of the Cell Innovation Program (S.I. and Y.H.) and the P-Direct (S.I.) from the MEXT, Japan; by Grants (S.I. and K.-i.T.) from the JSPS, Japan; by Grants-in-Aid (S.I.) from the MHLW, Japan; by the Program for Promotion of Fundamental Studies in Health Sciences (S.I.), NIBIO, Japan; by Grants from Takeda Science Foundation (S.I. and K.-i.T.), by a Grant from Yamaguchi Endocrine Research Foundation (K.-i.T.), Japan, by a Grant from Mochida Memorial Research Foundation (K.-i.T.), Japan.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/9/25
Y1 - 2015/9/25
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms9219
DO - 10.1038/ncomms9219
M3 - Article
C2 - 26404510
AN - SCOPUS:84942694022
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 8219
ER -
