Yin Yang 1 promotes the neuroendocrine differentiation of prostate cancer cells via the non-canonical WNT pathway (FYN/STAT3)

BackgroundA growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.MethodsUsing the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial-mesenchymal transition induction and neuroendocrine differentiation.ResultsAndrogen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non-canonical Wnt (FZD8/FYN/STAT3) pathway.ConclusionsWe identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in-depth investigation of the mechanism underlying YY1-mediated disease may lead to improved NEPC therapies. Androgen deprivation therapy stabilizes Yin Yang 1 (YY1) protein by inhibiting YY1 ubiquitination. In the nucleus, YY1 induces transcription by binding to the promoter-specific region of FZD8, which activates the non-canonical Wnt pathway at the cell membrane in association with Wnt9A, allowing phosphorylation of FYN as well as STAT3. Activated STAT3 signaling induces the expression of downstream neuroendocrine markers and epithelial-mesenchymal transition markers and promotes cell plasticity.image

Automated summary

YY1 is identified as a dysregulated transcription factor that plays a key role in neuroendocrine prostate cancer progression. Androgen deprivation therapy stabilizes YY1 protein, enhancing its transcriptional activity and promoting cellular plasticity through the non-canonical Wnt pathway.