Abstract
BAZ2A is the epigenetic repressor of rRNA genes that are transcribed by RNA Polymerase I. In prostate cancer (PCa), however, BAZ2A function was shown to go 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 that differ from the silencing of rRNA genes. While TAM domain mediates BAZ2A recruitment to rRNA genes, in PCa cells TAM domain is not required for the association with BAZ2A-regulated genes. Instead, BAZ2A-TAM domain in association with RNA mediates the interaction with the topoisomerase 2A (TOP2A) and the histone demethylase KDM1A, which have been previously implicated in aggressive PCa. TOP2A and KDM1A expression levels positively correlate with BAZ2A levels in both localized and aggressive PCa. Pharmacological inhibition of TOP2A and KDM1A activity upregulates the expression of BAZ2A-repressed genes implicated in PCa that are regulated by a class of inactive enhancers bound by BAZ2A. Our findings indicate that RNA-mediated interactions between BAZ2A and TOP2A and KDM1A regulate gene expression in PCa and may prove to be useful for the stratification of prostate cancer risk and treatment in patients.
Competing Interest Statement
The authors have declared no competing interest.
