Beyond Expression: Role of Phosphorylated Residues of EZH2 in Lineage Plasticity in Prostate Cancer

Area of Science:

• Epigenetics and Molecular Oncology
• Cancer Biology
• Pharmacology

Background:

• Treatment resistance remains a significant challenge in oncology, despite advances in targeted therapies.
• Nongenetic mechanisms, particularly phenotypic plasticity regulated by epigenetic factors, are increasingly recognized as drivers of therapy resistance.
• The epigenetic modifier enhancer of zeste homolog 2 (EZH2) plays a crucial role in prostate cancer progression and resistance.

Approach:

• This review examines the multifaceted role of EZH2 phosphorylation in regulating its canonical (PRC2-dependent) and noncanonical (PRC2-independent) functions.
• It explores how kinase-mediated phosphorylation of specific EZH2 residues impacts its activity, stability, and complex assembly.
• The review discusses the known contributions of EZH2 phosphorylation at S21, T350, and T311 in prostate cancer and treatment resistance.

Key Points:

• EZH2 phosphorylation modulates its function as both an epigenetic repressor via PRC2 and a transcriptional activator independently of PRC2.
• Elevated EZH2 activity and specific phosphorylation events are linked to castration-resistant prostate cancer and resistance to androgen receptor pathway inhibitors.
• Investigating the functional impact of other phosphorylated EZH2 residues may reveal novel therapeutic targets.

Conclusions:

• EZH2 phosphorylation is a critical regulatory mechanism influencing prostate cancer progression and therapeutic resistance.
• Targeting EZH2 phosphorylation sites presents a promising avenue for developing novel treatment strategies against resistant prostate cancers.
• Further research into the functional consequences of EZH2 phosphorylation is warranted to fully exploit its therapeutic potential.