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

Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylatedcytosine (5-hmC) is an epigenetic mark potentially important in cancer. Herewe 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 ofmethylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgenreceptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedlyenhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcomeof PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumourgrowth and increased TET2 expression in an animal model of HRPC. Interestingly, global5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmCactivates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directlylinks the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumourprogression.