Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Castration-resistant prostate cancer (CRPC) is an incurable malignancy often developing resistance to androgen receptor (AR) antagonist therapies like enzalutamide.
• Enhancer of zeste homolog 2 (EZH2), a component of the PRC2 complex, plays a crucial role in AR-mediated gene suppression and its activity increases in CRPC.

Purpose of the Study:

• To investigate the synergistic efficacy of combining an EZH2 inhibitor (GSK126) with an AR antagonist (enzalutamide) for treating CRPC.
• To elucidate the underlying molecular mechanisms of this combination therapy in CRPC cells.

Main Methods:

• CRPC cell lines (22Rv1 and C42B) were treated with GSK126 and enzalutamide, individually and in combination.
• Cell proliferation, cell cycle arrest, and cell death were assessed.
• Expression levels of AR, AR-v7, PSA, Akt, EZH2, SUZ12, EED, and H3K27 trimethylation were analyzed.

Main Results:

• The combination of GSK126 and enzalutamide demonstrated synergistic inhibition of CRPC cell proliferation and induced cell cycle arrest and increased cell death.
• This combination significantly downregulated AR and AR-v7 expression, reduced PSA levels, and inhibited Akt activity.
• Treatment led to decreased EZH2 and PRC2 complex component levels, loss of H3K27 trimethylation, and disrupted AR-PRC2 complex interaction.

Conclusions:

• Combined inhibition of EZH2 and AR presents a potent synergistic anticancer effect in CRPC.
• This dual-targeting strategy shows preclinical proof-of-concept, offering a novel therapeutic approach for CRPC treatment.