Nat Commun: EZH2 methylates ERG K362 and enhances the carcinogenic activity of TMPRSS2-ERG in prostate cancer

ETS transcription factors are a family of signal-dependent transcription regulators that control cell proliferation, differentiation and carcinogenesis
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Previous studies have shown that gene fusion of ETS factor ERG and androgen-regulated serine protease TMPRSS2 has been found in about half of prostate tumor patients, which is one of the most common gene recombinations in cancer

ETS transcription factors are a family of signal-dependent transcription regulators that control cell proliferation, differentiation and carcinogenesis

The TMPRSS2-ERG fusion provides a potential mechanism for androgen-induced ERG overexpression and transcriptome reprogramming of prostate epithelial cells
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However, the relevant mechanism of abnormal expression of ERG affecting tumor occurrence and development is still unclear

The TMPRSS2-ERG fusion provides a potential mechanism for androgen-induced ERG overexpression and transcriptome reprogramming of prostate epithelial cells

The study found an important mechanism that promotes the carcinogenic activity of ERG
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The researchers found that a specific lysine residue (K362) in the autoinhibitory domain of ERG can be methylated by EZH2

A specific lysine residue (K362) in the autoinhibitory domain of ERG can be methylated by EZH2

EZH2 methylation ERG K362

EZH2 methylation ERG K362

In the transgenic mouse model of ERG fusion-positive prostate cancer, ERG K362 methylation is associated with the loss of PTEN and the development of the disease to aggressive adenocarcinoma
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In ERG-positive VCaP cells and ERG/PTEN mice, the absence of PTEN can induce the activation of AKT and the phosphorylation of the 21st serine residue of EZH2, which is conducive to the methylation of ERG

K362 methylation affects protein conformation

K362 methylation affects protein conformation

Further research found that ERG can interact with EZH2 and occupy several sites in the genome together to form a transactivation complex
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Similarly, ERG/EZH2 co-regulated target genes can preferentially eliminate this regulatory effect in ERG-obtained and PTEN-deficient tumors and castration-resistant prostate cancer

ERG/EZH2 co-regulated target genes can preferentially eliminate this regulatory effect in tumors with ERG acquisition and PTEN deletion and castration-resistant prostate cancer

EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer.

 

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