EZH2: A Drug Target and Biomarker (G2146)

NCBI ID: G2146

EZH2

EZH2: A Drug Target and Biomarker

EZH2, also known as enhancer of zeste 2, is a key component of the polycomb repressive complex 2 (PRC2) that plays an important role in regulating gene expression through histone modification. PRC2, consisting of EZH2, EED, SUZ12, and RbAp46/48, methylates histone 3 at lysine 27 (H3K27me3), leading to chromatin compaction and gene silencing. However, studies have also revealed a PRC2-independent function of EZH2 in transcriptional activation.

Somatic mutations in EZH2 have been found to affect histone modification pathways. Mutant EZH2 loses its methylase activity, resulting in decreased H3K27me3 levels. This leads to loosening of histone proteins, allowing easier access for transcription factors and promoting genetic expression. Additionally, overexpression of PHF19, a protein that interacts with PRC2, has shown conflicting results in the mechanistic investigation of EZH2 function. Some studies suggest that PHF19 promotes PRC2 activity and represses cell cycle inhibitor genes, while others suggest that it impedes PRC2 activity by promoting the phosphorylation of EZH2, leading to EZH2 inactivation and increased expression of genes important in cancer progression.

Furthermore, AC1NOD4Q, a molecule that binds to the HOTAIR5' domain, weakens the recruitment and binding abilities of EZH2, inhibiting H3K27-mediated trimethylation and restoring expression of the NLK promoter. This highlights the potential of targeting the interaction between EZH2 and HOTAIR for reversing cancer progression and metastasis induced by HOTAIR.

In summary, EZH2 is a crucial component of PRC2 involved in chromatin compaction and transcriptional regulation through H3K27 methylation. Somatic mutations in EZH2 can disrupt this process, leading to altered gene expression. While EZH2 primarily functions as a transcriptional repressor, it also has PRC2-independent roles in transcriptional activation. Further investigations into the interactions and mechanisms involving EZH2, such as its interaction with PHF19 and HOTAIR, provide insights into potential therapeutic strategies for cancer treatment.
Based on the provided context information, some key viewpoints regarding EZH2 can be extracted:

EZH2 inhibition has shown promising results in alleviating liver fibrosis in rats.
EZH2 and SIRT1 play a role in maintaining endothelial homeostasis, and restoring the balance between these two proteins may have potential in preventing atherogenesis.
Epigenetic changes, including the downregulation of EZH2, are important during the osteogenic differentiation of AF-MSCs.
EZH2 is connected to deregulated metabolites in cervical cancer, and its regulation may be influenced by signaling pathway proteins, transcription factors, and miRNAs.
EZH2 repression leads to the absence of functional PPP2R2B-containing PP2A, contributing to tumorigenesis and potentially resistance to anti-HER2 therapy.

These viewpoints provide an overview of the diverse roles and implications of EZH2 in various biological contexts and diseases.

Protein Name: Enhancer Of Zeste 2 Polycomb Repressive Complex 2 Subunit

Functions: Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2 (PubMed:22323599, PubMed:30923826). Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes. EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA. Regulates the circadian clock via histone methylation at the promoter of the circadian genes. Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription

The "EZH2 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about EZH2 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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