Upregulation of YY1 in M2 macrophages promotes secretion of exosomes containing hsa-circ-0000326 via super-enhancers to facilitate prostate cancer progression.

Abstract

The transcription factor YY1 is significantly upregulated in M2 macrophages, which can facilitate the malignant progression of multiple cancers. However, the precise mechanisms underlying the influence of YY1-high M2 macrophages on prostate cancer (PCa) progression remain elusive. Therefore, this study aims to elucidate the specific mechanisms by which YY1-high M2 macrophages influence PCa progression. Cell proliferation was assessed through colony formation and CCK8 assays. To evaluate cell invasion and migration, Transwell and wound healing assays were utilized. We investigated the effects of exosomes derived from M2 macrophages overexpressing YY1 on PCa cells. Subsequently, circRNA microarrays and qRT-PCR identified a high level of hsa-circ-0000326 in exosomes. Nucleoplasmic isolation, luciferase reporter, RNA-pulldown assays elucidated the functions and downstream targets (miR-338-3p and AR) of hsa-circ-0000326. Chromatin immunoprecipitation sequencing, chromatin conformation capture, qRT-PCR, western blotting, and agarose-electrophoresis assays examined YY1's role in transcribing the hsa-circ-0000326 maternal gene MALAT1 as well as its modulation of QKI expression. Our results demonstrated that the secretion of exosomes enriched with hsa-circ-0000326 by YY1-overexpressing M2 macrophages contributes to PCa metastasis. Hsa-circ-0000326 functions as a competitive endogenous RNA against miR-338-3p to promote androgen receptor levels in PCa cells. Mechanistic investigations revealed that YY1 binds to the super-enhancer region of MALAT1 enhancing transcriptional activity for this gene. Simultaneously, YY1 upregulates QKI expression, facilitating splicing events leading to the formation of hsa-circ-0000326. Inhibiting exosomal hsa-circ-0000326 presents a potential therapeutic approach for treating metastatic PCa.