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.
Highlights
Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer
We established bicalutamide (AR antagonist)-resistant prostate cancer (BicR) cells derived from an Androgen receptor (AR)-positive, bicalutamide-sensitive LNCaP prostate cancer cell line (Supplementary Fig. 1a)
In LNCaP cells, a total of 44 micro RNAs (miRNAs) were significantly induced by DHT (41.2-fold), including representative AR-regulated miRNAs such as miR-125b24, miR-21 and miR-148a26, while 30 miRNAs were induced by DHT (41.2-fold) in BicR cells
Summary
Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. 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. Global 5-hmC modification regulated by miR-29b represses FOXA1 activity. DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression. The relationship between AR activity and DNA modifications, 5-mC hydroxylation, has not been described previously, and the role of androgen-targeted non-coding RNAs such as micro RNAs (miRNAs) in global epigenetic control is largely unknown. Our findings suggest that AR-modulated TET2 pathways form the basis of a new treatment strategy for advanced, HRPCs
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