YY1 complex in tumor-associated macrophage promotes prostate cancer progression by upregulating IL-6 [RNA-seq]

Tumor-associated macrophages are mainly polarized into the M2 phenotype, which remodels the tumor microenvironment and promotes tumor progression by secreting various cytokines. Herein, we reported that Yin Yang 1 (YY1) was highly expressed on tumor-infiltrated M2 macrophages in prostate cancer and was associated with poorer clinical outcomes. Using transgenic mice overexpressing YY1, we found that the tumor-promoting effects of oe-YY1 mice could be suppressed by macrophage depletion. Further in-vitro and in-vivo experiments using YY1 overexpressing and knocked down M2 macrophages demonstrated that YY1 induced M2 polarization and increased macrophages-induced prostate cancer progression by the IL-6/STAT3 pathway. Furthermore, YY1 promoted phase-separated condensates and upregulated IL-6 by modulating p300, p300 and CEBPB as a transcription complex. By conducting chromatin immunoprecipitation sequencing of M2 macrophages and monocytes, an M2-specific IL-6 enhancer associated with the YY1 complex was shown to upregulate IL-6 expression in M2 macrophages, and H3K27ac and YY1 signals significantly increased around this enhancer. In conclusion, YY1 complex promotes the M2 macrophages polarization and upregulates IL-6 in macrophages by inducing phase separation and a M2-specific enhancer, thereby increasing prostate cancer progression. These findings might lead to novel therapies targeting YY1 in prostate tumor-associated macrophages. We performed gene expression profiling analysis using data obtained from RNA-seq of 2 different cells. Comparative gene expression profiling analysis of RNA-seq data for oe/nc-YY1 M2 macrophages CM cocultured LNCaP cells