BAZ2A-RNA mediated association with TOP2A and KDM1A represses gene expression in prostate cancer

Abstract

BAZ2A is the repressor of rRNA genes that are transcribed by RNA Polymerase I. In prostate cancer (PCa), however, BAZ2A function goes beyond this role since it can also repress other genes that are frequently silenced in metastatic disease. However, the mechanisms of BAZ2A-mediated repression in PCa remain elusive. Here we show that BAZ2A represses genes implicated in PCa through its RNA-binding TAM domain using mechanisms differing from rRNA gene silencing. While TAM domain mediates BAZ2A recruitment to rRNA genes, in PCa cells this is not required for BAZ2A association with target genes. Instead, BAZ2A-TAM domain in association with RNA mediates the interaction with topoisomerase 2A (TOP2A) and histone demethylase KDM1A, whose expression positively correlates with BAZ2A levels in both localized and aggressive PCa. Pharmacological inhibition of TOP2A and KDM1A activities upregulates the expression of BAZ2A-repressed genes that are regulated by a class of inactive enhancers bound by BAZ2A whereas rRNA genes are not affected. Our findings showed a novel RNA-based mechanism of gene regulation in PCa. Further, the data indicate that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A repress genes critical to PCa and may prove to be useful to stratify prostate cancer risk and treatment in patients.