Antagonistic action of a synthetic androgen ligand mediated by chromatin remodeling in a human prostate cancer cell line

• Published in: Biochemical and biophysical research communications 2022-07, Vol.612, p.110-118
• Main Authors: Sawada, Takahiro, Kanemoto, Yoshiaki, Amano, Rei, Hayakawa, Akira, Kurokawa, Tomohiro, Mori, Jinichi, Kato, Shigeaki
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - pharmacology; Androgen receptor; Androgen Receptor Antagonists - pharmacology; Androgens - pharmacology; Antagonist; Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly; Chromatin remodeling; Dihydrotestosterone - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Ligands; Male; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.04.109

The clinical use of androgen receptor (AR) antagonists has been successful in treating prostate cancer patients, inducing remission of androgen-dependent tumors. However, a couple of years after treatment, prostate tumors transition into an androgen-independent state with altered gene expression profiles, but the molecular basis is not understood. Since the AR antagonists trigger this transition, we assessed whether AR antagonists induce chromatin reorganization in an androgen-dependent prostate cancer cell line (LNCaP). Treatment of LNCaP cells with two clinically used AR antagonists (bicalutamide [Bic] and enzalutamide [Enz]) expectedly resulted in antagonistic effects on cell proliferation, AR transactivation, and dihydrotestosterone (DHT)-induced expression of AR target genes. Thus, the antagonists expectedly acted to antagonize the transactivation function of AR activated by androgen binding. By ChIP-qPCR assay, AR bound to Bic, but not Enz, was recruited to an endogenous consensus AR-binding site within the kallikrein-related peptidase 3 gene promoter after treatment with Bic, similar to the effect of DHT. By ATAC-seq analysis of the cells after long-term treatment for 5 days, Bic and dihydrotestosterone DHT induced different chromatin reorganization patterns and gene expression profiles, suggesting that Bic exhibited a distinct action from that by DHT. Thus, these results suggest that the action of a known AR antagonist is mediated by chromatin reorganization in a prostate cancer cell line. •An androgen antagonist (Bicalutamide) was potent to remodel chromatin configuration in human prostate cancer cell line.•The pattern in chromatin reorganization induced by Bicalutamide was not identical from that by dihydrotestosterone (DHT).•Gene expression profile and cellular events were different between in the cells treated with Bicalutamide and DHT.•The present findings provide a molecular basis for malignant progression of prostate cancer in the treated patients.