# SMARCA4 promotes lineage plasticity and enzalutamide resistance in prostate cancer by regulating PROX1 via H3K27 acetylation

## TL;DR

This study shows that SMARCA4 promotes prostate cancer resistance to enzalutamide by regulating PROX1 through epigenetic changes, offering a new therapeutic target.

## Contribution

The study identifies SMARCA4 as a novel driver of enzalutamide resistance and NEPC progression via its regulation of PROX1 through H3K27 acetylation.

## Key findings

- SMARCA4 is upregulated in enzalutamide-resistant prostate cancer cells.
- SMARCA4 promotes neuroendocrine transformation by enhancing PROX1 expression via H3K27ac.
- Inhibiting SMARCA4 or using HDACi reverses aggressive tumor characteristics.

## Abstract

Enzalutamide resistance is a dynamic process often culminating in the aggressive progression to neuroendocrine prostate cancer (NEPC). This lineage plasticity is hypothesized to be driven by underlying epigenetic alterations, yet the core molecular drivers remain unclear. Elucidating these factors is of significant clinical importance for overcoming resistance. To model this transition, we established a dynamic gradient-resistant cell model simulating the clinical response to enzalutamide, and found robust upregulation of the chromatin remodeling factor SMARCA4 in resistant cells. Both in vitro and in vivo experimental results demonstrated that inhibiting SMARCA4 effectively suppresses tumor progression and reverses neuroendocrine transformation. Mechanistically, integrated multi-omics analysis, correlation studies, and protein interaction experiments revealed the transcription factor PROX1 as a crucial downstream target of SMARCA4, where its inhibition alone was sufficient to reverse the aggressive malignancy and neuroendocrine characteristics of resistant cells. We further demonstrated that SMARCA4 enhances H3K27ac levels and chromatin accessibility at the PROX1 locus to regulate its expression. Importantly, the tumor-suppressive effect of SMARCA4 knockdown could be rescued by histone deacetylase inhibitors (HDACi), achieving a level of recovery comparable to PROX1 overexpression. In summary, this study defines a core epigenetic pathway, showing that increased SMARCA4 activity promotes luminal-to-neuroendocrine transformation by enhancing histone acetylation and chromatin accessibility at the PROX1 locus. Targeting the SMARCA4-PROX1 axis provides a valuable therapeutic strategy for combating enzalutamide resistance and NEPC progression.