Interaction between ZMIZ2 and AR promotes prostate cancer proliferation in vitro and in vivo.

Abstract

Background: ZMIZ2, an androgen receptor (AR) transcriptional co-regulator, promotes prostate cancer (PCa) cell proliferation by interacting with AR to upregulate genes associated with cell proliferation; however, its specific cooperative mechanisms remain unclear. This study aims to elucidate these mechanisms.

Materials and methods: We analyzed the expression level and prognostic significance of ZMIZ2 in PCa using bioinformatics methods. ZMIZ2 expression and its correlation with the Gleason score were analyzed using clinical samples. LNCaP cells with ZMIZ2 overexpression or AR knockdown were employed to evaluate cell proliferation. RNA-seq, qPCR, Western blot, and co-immunoprecipitation were used to explore the molecular mechanisms. In vivo xenograft models were utilized to validate the effects.

Results: ZMIZ2 expression was significantly higher in PCa tissues and positively correlated with the Gleason score. Overexpressing ZMIZ2 robustly promoted LNCaP cell growth, but this promoting effect was dramatically lessened in the absence of AR expression. Mechanistically, ZMIZ2 recruited multiple acetyltransferases and formed a transcriptional complex with the N-terminal domain of AR, which bound to the promoters of cell cycle-related genes CDK1, CCNA2, and CCNE2, leading to upregulated transcription. Both in vitro cell culture experiments and in vivo models supported ZMIZ2's role in promoting proliferation.

Conclusion: ZMIZ2 promotes PCa cell proliferation through the AR signaling pathway by regulating key cell-cycle genes, highlighting it as a potential therapeutic target.