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

## TL;DR

ZMIZ2 interacts with the androgen receptor to promote prostate cancer cell growth by activating genes linked to cell proliferation.

## Contribution

This study identifies the functional domain and spatial conformation of ZMIZ2-AR interaction, revealing a novel mechanism for prostate cancer progression.

## Key findings

- ZMIZ2 expression is elevated in prostate cancer tissues and correlates with higher Gleason scores.
- ZMIZ2 promotes cell proliferation by recruiting acetyltransferases and forming a complex with AR's N-terminal domain.
- The ZMIZ2-AR complex activates cell cycle genes CDK1, CCNA2, and CCNE2, driving prostate cancer progression.

## Abstract

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.

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.

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.

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

This study identified the functional domain of the interaction between ZMIZ2 and AR protein and elucidated its spatial conformation, laying a structural foundation for revealing the mechanism by which ZMIZ2 synergizes with AR signaling to promote the progression of prostate cancer (PCa).This study demonstrated that in PCa cells, ZMIZ2, as a transcriptional co-regulator of AR, recruits acetyltransferases to bind to AR, upregulates the transcriptional activity of downstream target genes, and activates AR signaling, revealing the molecular mechanism by which AR signaling promotes the progression of PCa.This study provides a new theoretical basis and potential molecular targets for PCa treatment strategies targeting the interaction between ZMIZ2 and AR, with significant translational medical value.

This study identified the functional domain of the interaction between ZMIZ2 and AR protein and elucidated its spatial conformation, laying a structural foundation for revealing the mechanism by which ZMIZ2 synergizes with AR signaling to promote the progression of prostate cancer (PCa).

This study demonstrated that in PCa cells, ZMIZ2, as a transcriptional co-regulator of AR, recruits acetyltransferases to bind to AR, upregulates the transcriptional activity of downstream target genes, and activates AR signaling, revealing the molecular mechanism by which AR signaling promotes the progression of PCa.

This study provides a new theoretical basis and potential molecular targets for PCa treatment strategies targeting the interaction between ZMIZ2 and AR, with significant translational medical value.

This study focuses on prostate cancer (PCa), a malignancy of the prostate epithelium. As a transcriptional co-regulator of the androgen receptor (AR), ZMIZ2 plays an important role in the proliferation process of PCa cells. Bioinformatics analysis reveals its elevated expression in PCa tissues, positively correlated with the Gleason score. In vitro and in vivo experiments have demonstrated that ZMIZ2 promotes the proliferation of PCa cells in an AR signaling-dependent manner. Mechanistically, as depicted in the figure, ZMIZ2 recruits acetylases (e.g. HAT1, KAT6B, EP300) and binds to AR's NTD. This complex binds to ARE near cell-cycle gene (CDK1, CCNA2, CCNE2) promoters, upregulating transcription via the AR pathway and driving PCa cell proliferation.