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An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.

Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, but how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing, we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated dedifferentiation program.

Pubmed ID: 20478527

Authors

  • Yu J
  • Yu J
  • Mani RS
  • Cao Q
  • Brenner CJ
  • Cao X
  • Wang X
  • Wu L
  • Li J
  • Hu M
  • Gong Y
  • Cheng H
  • Laxman B
  • Vellaichamy A
  • Shankar S
  • Li Y
  • Dhanasekaran SM
  • Morey R
  • Barrette T
  • Lonigro RJ
  • Tomlins SA
  • Varambally S
  • Qin ZS
  • Chinnaiyan AM

Journal

Cancer cell

Publication Data

May 18, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: 1R01CA132874-01A1
  • Agency: NHGRI NIH HHS, Id: 1R01HG005119
  • Agency: NCI NIH HHS, Id: K99 CA129565
  • Agency: NCI NIH HHS, Id: K99 CA129565-02
  • Agency: NCI NIH HHS, Id: K99 CA129565-02S1
  • Agency: NCI NIH HHS, Id: K99CA129565-01A1
  • Agency: NCI NIH HHS, Id: P50 CA069568
  • Agency: NCI NIH HHS, Id: P50 CA069568-06A10016
  • Agency: NCI NIH HHS, Id: P50 CA069568-06A19001
  • Agency: NCI NIH HHS, Id: P50 CA069568-110020
  • Agency: NCI NIH HHS, Id: P50CA090386
  • Agency: NCI NIH HHS, Id: P50CA69568
  • Agency: NCI NIH HHS, Id: R01 CA132874
  • Agency: NCI NIH HHS, Id: R01 CA132874-01A1
  • Agency: PHS HHS, Id: U01 111275
  • Agency: NCI NIH HHS, Id: U01 CA111275
  • Agency: NCI NIH HHS, Id: U01 CA111275-01
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins
  • Disease Progression
  • Gene Fusion
  • Humans
  • Male
  • Oncogene Proteins, Fusion
  • Polycomb Repressive Complex 2
  • Prostatic Neoplasms
  • Receptors, Androgen
  • Signal Transduction
  • Transcription Factors