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

Abstract

Despite the development of effective targeted therapies and a significant understanding of carcinogenesis and cancer progression, treatment resistance is a major obstacle in achieving durable long-term control in many types of cancers. Emerging evidence supports that nongenetic mechanisms could play an underappreciated role in therapy resistance. These mechanisms include phenotypic plasticity, which is recognized as a hallmark of cancer and translates to epigenetic and transcriptional control of gene expression. Alterations in the expression and activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2) support prostate cancer lineage plasticity and progression. EZH2 expression and activity is elevated in castration-resistant prostate cancer treated with androgen receptor pathway inhibitors and in treatment-resistant prostate cancer. Moreover, 17 known residues of EZH2 are phosphorylated on by multiple kinases that modulate its activity, localization, stability, and polycomb repressive complex (PRC2) assembly. In this review, we explore the contribution of EZH2 phosphorylation in regulating canonical PRC2 in a methylation-dependent manner as an epigenetic repressor and in a noncanonical manner independent of PRC2 as a transcription activator. Apart from the contribution of EZH2 phosphorylation at serine 21, threonine 350, and threonine 311 in prostate cancer progression and treatment resistance, we discuss how other EZH2 phosphorylated residues with unknown functions could contribute to prostate cancer based on their upstream regulators and potential therapeutic utility.

• Authors: Shaghayegh Nouruzi, Nakisa Tabrizian, Amina Zoubeidi
• Journal: Endocrinology (Endocrinology) Vol. 164 Issue 4 (02 11 2023) ISSN: 1945-7170 [Electronic] United States
• PMID: 36718085 (Publication Type: Review, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• EZH2 protein, human

Topics

• Male
• Humans
• Enhancer of Zeste Homolog 2 Protein (genetics)
• Polycomb Repressive Complex 2 (genetics)
• Prostatic Neoplasms (metabolism)
• Methylation
• Carcinogenesis (genetics)
• Gene Expression Regulation, Neoplastic