Matrix stiffness modulates androgen response genes and chromatin state in prostate cancer.

Abstract

The interplay between the extracellular matrix (ECM) and prostate cancer has been shown to increase ECM stiffness, correlating with more aggressive disease forms. However, the impact of ECM stiffness on the androgen receptor (AR), a key target in prostate cancer treatment, remains elusive. Here, we investigated whether matrix stiffness influences prostate cancer progression, transcriptional regulation, chromatin state, and AR function in AR-positive prostate cancer cells under varying ECM stiffness conditions. We utilized ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA sequencing under different ECM conditions, along with the SUC2 metastatic prostate adenocarcinoma patient dataset, to investigate the role of ECM stiffness in chromatin state and androgen response genes, as well as its impact on prostate cancer progression. Results demonstrated that increased ECM stiffness elevated the expression of genes related to proliferation and differentiation. In contrast, androgen response genes were most highly induced in soft ECM conditions. Integrating chromatin accessibility with transcriptomic data revealed that androgen response genes were more transcriptionally available in soft ECM conditions. Additionally, increased ECM stiffness upregulated genes associated with low overall survival in the SUC2 dataset. Taken together, our results indicate that high expression of hard matrix stiffness genes may promote prostate cancer progression, leading to more aggressive disease forms associated with poor survival.