Activation of theAndrogen Receptorgene by BORIS/CTCFL in prostate cancer cells

AbstractBORIS/CTCFL, a paralogue of the chromatin architectural protein CTCF, is a member of the cancer-testis antigen family, normally present in the testes. BORIS is expressed in various tumours, including prostate cancers, however the function of BORIS in cancer cells is not well defined. The androgen receptor (AR) plays a critical role in the normal development of a human prostate gland and pathogenesis of prostate cancer. In our previous study we described a positive correlation between elevated levels of BORIS and AR in prostate cancers, and activation of theARgene by BORIS in prostate cancer cells. Elucidation of the mechanisms involved in the modulation of AR activity is important to understand prostate tumourigenesis and investigation of transcriptional regulation of theARgene by BORIS may provide new insights into this issue. Here we report the ability of BORIS to not only positively regulateARin androgen-dependent prostate cancer (ADPC) cells, but re-activate epigenetically silencedARin androgen-independent prostate cancer (AIPC) cells leading to the production of biologically active AR protein. CTCF, on the other hand, had repressive effects on theAR. In both, ADPC and AIPC cells, introduction of ectopic BORIS was associated with the reduction in theARpromoter methylation, increase in active and decrease in repressive chromatin marks, and decrease in CTCF occupancies at the two main upstream BORIS/CTCF binding sites. We propose a model of epigenetic regulation ofARby BORIS in prostate cells whereby BORIS remodels the chromatin at theARpromoter leading to transcriptional activation.