XAF1 is a tumor suppressor gene with low or absent expression in cancer. Since transcriptional reactivation or ectopic-mediated expression of XAF1 inhibits tumor growth, it is of great interest to elucidate the molecular mechanisms leading to XAF1 silencing. YY1 is a transcription factor that acts as a repressor or an activator to modulate several cancer-associated cellular processes. Both YY1 and XAF1 have key roles in prostate cancer (PCa) progression and are associated with worse clinical outcomes. To assess whether YY1 regulates the transcriptional activation of the XAF1 gene, we performed gene-reporter assays coupled with site-directed mutagenesis, which showed that YY1 is able to mediate XAF1 silencing. Concordantly, ChIP-qPCR assays showed that YY1 interacts with the XAF1 promoter in PC3 cells that lacks XAF1 expression. This association was lost after exposure to epigenetic modulators that induce XAF1 expression. Further supporting the YY1's repressive role, we found transcriptional reactivation of the XAF1 gene by YY1 downregulation. As expected by previous reports showing that HDAC1 is needed for YY1-mediated repressive actions, we observed XAF1 re-expression after either inhibition or downregulation of the HDAC1 gene. Finally, expression data retrieved from the TCGA consortium showed that PCa samples presented lower XAF1 and higher HDAC expression levels than normal tissues. Thus, our results support a model in which YY1 is able to silence tumor suppressor genes such as XAF1 through HDAC1 in PCa. (C) 2018 Elsevier Inc. All rights reserved.