The androgen receptor (AR) is a pleiotrophic transcription factor that regulates expression of a large number of genes involved in many diverse cellular processes. The AR activation pathways have been studied extensively. However, the molecular mechanism and biological significance of AR inhibitory signals remain poorly understood. Mukhopadhyay et al. have now identified the nuclear matrix protein scaffold attachment factor B1 (SAFB1) as a novel AR corepressor. The authors found that SAFB1 physically associates with AR protein and inhibits AR transcriptional activity and androgen-sensitive gene expression. SAFB1 had no effect on chromatin occupancy of AR, but silencing of SAFB1 abolished recruitment MST1, a known AR repressor, at AR target loci. They also showed that SAFB1 interacts with EZH2, SUZ12 and EED, three core components of the Polycomb repressive complex 2 (PRC2), which catalyzes the gene repression histone modification H3 lysine 27 trimethylation (H3K27me3). The authors further showed that forced expression of SAFB1 increases H3K27me3 at AR target loci and this effect requires EZH2. Finally, the authors demonstrated that expression of SAFB1 is downregulated in human prostate cancer (PCa) specimens and SAFB1 knockdown results in an aggressive phenotype of PCa. These findings identify SAFB1 as an important node for integration of multiple inhibitory signals of AR, which represents a viable pathway for therapeutic intervention of PCa.

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