EZH2 and Associated Diseases

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Overview of EZH2

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by the EZH2 gene in humans. EZH2 participates in the progress of histone methylation and causes transcriptional repression finally. EZH2 can methylate the histone H3 at lysine 27 which silences the gene function by forming heterochromatin. EZH2 is regarded as the functional enzymatic component in the polycomb repressive complex 2 (PRC2) which regulates embryonic development and differentiation by epigenetic regulation.

EZH2 in Disease

Mutation or overexpression of EZH2 is associated with many forms of cancer including breast cancer, hepatocellular cancer, and so on. Mutations of the EZH2 gene are involved in weaver syndrome. EZH2 is also related to neurodegenerative symptoms.

  • Hepatocellular carcinoma

Overexpression of EZH2 is associated with the malignant progression of hepatocellular carcinoma (HCC). The expression distribution of EZH2 is located in the hepatocytes of HCC, not in the normal livers. In the EZH2-overexpressing cultured carcinoma cells, the knockdown of EZH2 by siRNA affects the proliferation rate. Overexpression of EZH2 is associated with vascular and lymphatic invasion of HCC and speeds up the malignant progression of HCC. EZH2 could thus be a target against advanced HCC.

  • B-cell lymphomas

Mutation of EZH2 is related to human B-cell lymphoma (BCL). Heterozygous mutant EZH2 is associated with BCL. As the catalytic subunit of the PRC2 complex, EZH2 can catalyze the histone H3K27 trimethylation for the transcriptional inhibition of target genes. Point mutations of the EZH2 gene at Tyr641 will ablate the enzymatic activity and fail to methylate the unmodified substrate. EZH2 overexpression causes transcriptional repression and is difficult in the demethylation of H3K27me3. In BCL tumors, EZH2 is positively correlated with cell proliferation, and EZH2 target genes are negatively linked to proliferation. The combination of wild type and mutant EZH2 causes the H3K27me3 in proper sites in human BCL.

Overexpression of EZH2 can catalyze the histone H3K27 trimethylation causing transcriptional suppression Fig.1 Overexpression of EZH2 can catalyze the histone H3K27 trimethylation causing transcriptional suppression. (Sneeringer, 2010)

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References

  1. Sasaki, M.; et al. The overexpression of polycomb group proteins Bmi1 and EZH2 is associated with the progression and aggressive biological behavior of hepatocellular carcinoma. Lab Invest. 2008,88: 873–882.
  2. Sneeringer, C. J.; et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl. Acad. Sci. U.S.A. 2010, 107: 20980–20985.
For research use only. Not intended for any clinical use.