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The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2

L Beke1, M Nuytten, A Van Eynde

  • 1Laboratory of Biosignaling & Therapeutics, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, Leuven, Belgium.

Oncogene
|January 24, 2007
PubMed

Insights

Prostate cancer cells lose the tumor suppressor PSP94 due to EZH2 activity. EZH2 silences the MSMB gene via histone modifications, driving advanced prostate cancer progression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • Prostatic Secretory Protein 94 (PSP94) suppresses tumor growth and metastasis.
  • PSP94 expression is lost in advanced, hormone-refractory prostate cancer.
  • This loss correlates with increased expression of Polycomb protein EZH2.

Purpose of the Study:

  • To investigate the causal relationship between EZH2 and MSMB gene silencing in prostate cancer.
  • To elucidate the epigenetic mechanisms underlying MSMB repression in advanced prostate cancer.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to assess EZH2 binding to the MSMB gene.
  • RNA interference (RNAi) to knock down EZH2 expression.
  • Overexpression of EZH2 to study its effect on MSMB expression.
  • Analysis of histone modifications (H3K27 trimethylation, H3K9 hypoacetylation) and DNA methylation.

Main Results:

  • The MSMB gene, encoding PSP94, is trimethylated on H3K27 in androgen-refractory prostate cancer cells.
  • EZH2 directly associates with the MSMB gene.
  • Knockdown of EZH2 increases MSMB expression, while EZH2 overexpression decreases it.
  • MSMB is further repressed by H3K9 hypoacetylation and promoter CpG island hypermethylation.

Conclusions:

  • EZH2 silences the tumor suppressor gene MSMB in advanced prostate cancer cells.
  • This silencing occurs through H3K27 trimethylation, H3K9 hypoacetylation, and promoter hypermethylation.
  • A novel link between the oncogene EZH2 and the tumor suppressor PSP94 is established.

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