EZH2

EZH2 (Enhancer of Zeste Homolog 2) is a member of the Polycomb-group proteins and functions as a histone methyltransferase. It is a critical component of the Polycomb Repressive Complex 2 (PRC2), which plays a key role in the epigenetic regulation of gene expression.

Structure

Diagram of the EZH2 SET domain.

EZH2 contains several important domains, including the SET domain, which is responsible for its methyltransferase activity. The SET domain catalyzes the transfer of methyl groups to lysine 27 of histone H3 (H3K27), leading to transcriptional repression of target genes.

Function

Mechanism of lysine methylation by S-adenosylmethionine (SAM).

EZH2 primarily functions as a histone methyltransferase, catalyzing the trimethylation of H3K27. This modification is associated with the formation of heterochromatin and the repression of gene expression. EZH2 is involved in various biological processes, including cell cycle regulation, stem cell maintenance, and cancer progression.

Role in Cancer

EZH2 is frequently overexpressed in various types of cancer, including prostate cancer, breast cancer, and lymphoma. Its overexpression is often associated with poor prognosis and aggressive tumor behavior. EZH2 contributes to oncogenesis by silencing tumor suppressor genes and promoting cell proliferation.

Inhibition and Therapeutic Targeting

Chart of EZH2 inhibitors.

Due to its role in cancer, EZH2 is a target for therapeutic intervention. Several small molecule inhibitors have been developed to target the methyltransferase activity of EZH2, aiming to reactivate silenced tumor suppressor genes and inhibit tumor growth.

Genetic and Epigenetic Regulation

Gene tree of EZH2.

The expression and activity of EZH2 are tightly regulated at both the genetic and epigenetic levels. Mutations in the EZH2 gene can lead to altered enzymatic activity and have been implicated in various diseases. Epigenetic modifications, such as DNA methylation and histone modifications, also influence EZH2 expression and function.

Mechanism of Action

Active site residues of EZH2.

EZH2 exerts its function through the methylation of histone H3 at lysine 27. This modification is recognized by other proteins that contribute to chromatin compaction and gene silencing. The precise mechanism involves the recruitment of PRC2 to target genes, where EZH2 catalyzes the methylation reaction.

Research and Future Directions

Research on EZH2 continues to uncover its diverse roles in development and disease. Understanding the precise mechanisms by which EZH2 regulates gene expression and contributes to disease pathogenesis is crucial for developing effective therapeutic strategies.

Related pages

• Polycomb-group proteins
• Histone methylation
• Epigenetics
• Cancer epigenetics