Prostate Cancer and EZH2 Signaling

Enhancer of zeste homolog 2 (EZH2), a member of the Polycomb group (PcG) proteins, functions as a fundamental component of the polycomb repressive complex 2 (PRC2), with two other core subunits. The enzyme has histone methyltransferase (MTase) activity, which selectively facilitates the methylation of histone 3 lysine 27 (H3K27) on promoters of target genes. PRC2 functions as epigenetic silencers that have considerable importance in maintaining cellular identity and preserving the pluripotency of embryonic stem cells. Over the course of the last 20 years, a growing body of data has provided support for the presence of mutations in the EZH2 gene and/or its upregulation in several hematological malignancies and solid tumors, particularly prostate cancer. Moreover, EZH2 is known as one of the most increased genes in neuroendocrine prostate tumors, which exhibit increased abundance as a result of the therapeutic administration of high-affinity inhibitors targeting the androgen receptor system. Numerous studies have shown the epigenetic roles of EZH2 in the silencing of tumor suppressor factors and the facilitation of carcinogenesis. However, there have been reports of inconsistencies between EZH2 and H3K27 methylation. Moreover, the effectiveness of enzyme inhibitors targeting EZH2 in prostate cancer has been demonstrated to have constraints, highlighting the need for a more thorough understanding of the many activities of EZH2. In this chapter, we will begin by examining the regulatory mechanisms that govern the classical activities of EZH2 as a histone methyltransferase (MTase). Additionally, we will provide an overview of the multiple mechanisms engaged in bringing the PRC2 to the chromatin. Furthermore, in this chapter, we provide a comprehensive overview of other substrates of EZH2 that are not histones. Additionally, we examine the impact of post-translational changes on EZH2, which may influence its substrate selectivity. In conclusion, we provide a summary of the additional roles of EZH2 that go beyond its role as an MTase and/or a component of the PRC2. Specifically, we highlight its involvement as a transcriptional cofactor and explore the potential for therapeutic targeting of EZH2 in the context of prostate cancer.