BAZ2A association with H3K14ac is required for the transition of prostate cancer cells into a cancer stem-like state

Abstract

<jats:title>Abstract</jats:title><jats:p>Prostate cancer (PCa) is one of the most prevalent cancers in men. Cancer stem cells are thought to be associated with PCa relapse and represent a target against metastatic PCa. Here we show that BAZ2A (also known as TIP5), a factor previously implicated in aggressive PCa, is required for the dedifferentiation of PCa cells into a cancer stem-like state. We found that BAZ2A genomic occupancy in PCa cells coincides with H3K14ac enriched chromatin regions. This association is mediated by BAZ2A bromodomain (BAZ2A-BRD) that specifically binds to H3K14ac. In PCa cells, BAZ2A-BRD is required for the interaction with a class of inactive enhancers that are marked by H3K14ac and represses transcription of genes implicated in developmental and differentiation processes that are frequently silenced in aggressive and dedifferentiated PCa. BAZ2A-mediated repression of these genes is also linked to the histone acetyltransferase EP300 that acetylates H3K14ac. Mutations of BAZ2A-BRD or treatment with chemical probes that abrogate BAZ2A-BRD association with H3K14ac impair the dedifferentiation of PCa cells into a stem-like state. Furthermore, pharmacological inactivation of BAZ2A-BRD impairs the oncogenic transformation mediated by <jats:italic>Pten</jats:italic>-loss in prostate organoids. Our findings indicate a role of BAZ2A-BRD in PCa stem cell features and suggest potential epigenetic-reader therapeutic strategies to target BAZ2A in aggressive PCa.</jats:p>

BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer

“…These results indicate that the interaction with these target loci is not mediated by BAZ2A-TAM domain. Further, they support previous data showing that it is the BAZ2A-BRD domain to be required for the interaction of these regions that are enriched in H3K14ac (Peña-Hernández et al, 2021). Consistent with previous results (Mayer et al, 2006), the ChIP analysis showed that the interaction of BAZ2AΔTAM with the promoter of rRNA genes was reduced compared to BAZ2AWT (Fig.…”

“…KDM1A inhibitors upregulated the expression of genes linked to inactive BAZ2A-bound C2enhancers that are characterized by low H3K4me1 and H3K27ac levels (Peña-Hernández et al, 2021). KDM1A is highly expressed in various human malignancies and its activities were linked to carcinogenesis, making it a possible target for anticancer treatments (Maiques-Diaz and Somervaille, 2016).…”

“…TOP2A and KDM1A associate with BAZ2A via TAM domain and RNA and regulate the expression of BAZ2A-repressed genes in PC3 cells Previous BAZ2A-ChIPseq analyses in PC3 cells determined that BAZ2A associates with a class of inactive enhancers that are enriched in histone H3 acetylated at Lysin 14 (H3K14ac) and depleted of H3K27ac and H3K4me1 (Peña-Hernández et al, 2021). This group of inactive enhancers was termed as class 2 (C2)-enhancers.…”

“…3d). Similarly, the interaction with the promoter of AOX1, a known BAZ2A-regulated gene (Gu et al, 2015;Peña-Hernández et al, 2021), was not affected. These results indicate that the interaction with these target loci is not mediated by BAZ2A-TAM domain.…”

“…All cells were regularly tested for mycoplasma contamination. The F/H-BAZ2A PC3 cell line was described in (Peña-Hernández et al, 2021) Construct design cDNA corresponding to HA-FLAG tagged mouse wild type BAZ2A (H/F-BAZ2AWT), CopGFP and shBAZ2A for human BAZ2A were cloned into DC-DON-SH01 vector (GeneCopoeia).…”