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
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 -