THE NONCANONICAL WNT PATHWAY (FYN/STAT3) ACTIVATED BY YY1 PROMOTES THE NEUROENDOCRINE DIFFERENTIATION OF PROSTATE CANCER CELLS.

Abstract

Introduction

A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumors. Here we aimed to uncover the underlying mechanisms by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.

Methods

Bioinformatics analysis was performed to determine the expression of YY1 in different types of prostate cancer. Aberrant YY1 expression was validated in PCa tissues and cell lines via qRT-PCR. In vitro and in vivo functional experiments were performed to evaluate the role of YY1 in PCa malignancy. RNA sequencing, luciferase reporter assay and ChIP-PCR were used to identify the key downstream genes regulated by YY1. Ubiquitination modification and interaction between proteins were detected via Co-IP and western blotting.

Results

Using the TCGA and GEO databases, we bioinformatically analyzed the expression of YY1 in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via RT qPCR, western blotting, and IHC. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Bioinformatics analysis revealed aberrant YY1 expression in primary PCa, which was further validated in CRPC and NEPC tissues. Proliferation and metastasis of PCa cells were demonstrated in vitro and in vivo by functional assays. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells through epithelial-mesenchymal transition (EMT) induction and NE differentiation. Mechanically, androgen deprivation therapy (ADT) induces a decrease in ubiquitination of YY1 protein, enhances its stability, and thus enhances the transcriptional activity of FZD8. Castration enhances the binding of FZD8 to Wnt9A and mediates cellular plasticity by activating the noncanonical Wnt (FZD8/FYN/STAT3) pathway.

Conclusions

We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We hypothesize that an in-depth investigation of the underlying mechanisms of YY1-mediated disease may lead to improved NEPC therapies.