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 non-genetic mechanisms could play an underappreciated role in therapy resistance. These mechanisms include phenotypic plasticity, which is recognized as one of the hallmarks 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 (AR) 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 non-canonical 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.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

“…2, E and F ), underlining their pivotal role in cell survival and aggressiveness within their respective lineages. Drawing from the well-established roles of oncogenic TFs like AR and ASCL1 in PCa progression (17, 23), our investigation delved into the potential contributions of novel lineage-related TFs to cellular growth and aggressiveness. By identifying 10 novel AD-TF candidates (NFIX, THRB, ZNF613, ZNF614, ZNF615, CREB3L1, SIX5, ZBTB42, ZNF350, ZNF649) and 19 novel NE-TF candidates (AHDC1, CIC, CXXC4, DLX5, DLX6, DNMT1, HOXB3, HOXB7, HSF2, MAF, NKX2-2, NR1D2, RBPJ, SALL2, SATB1, ST18, TP73, ZNF367, ZNF711), we expanded the repertoire of potential therapeutic targets.…”

“…Moreover, TFs like FOXA1, NKX3.1, and MYC have emerged as key players in prostatic adenocarcinoma ( 20–22 ). Similarly, TFs such as ASCL1, BRN2, FOXA2, and ONECUT2 ( 23–26 ) are pivotal in NEPC, further underscoring the importance of TFs in disease biology. Despite these advancements, of the total 1639 TFs encoded by the human genome ( 27 ), only a minority have been associated with PRAD and NEPC.…”