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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

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Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex

Vivekananda Kedage1, Brady G Strittmatter1, Paige B Dausinas2

  • 1From the Departments of Molecular and Cellular Biochemistry and.

The Journal of Biological Chemistry
|September 10, 2017
PubMed

Insights

Phosphorylation of the ERG oncoprotein by ERK is crucial for prostate cancer progression. This study reveals how ERG phosphorylation by ERK activates cancer-promoting genes and cell migration, offering new therapeutic targets.

Area of Science:

  • Molecular Oncology
  • Cancer Biology
  • Prostate Cancer Pathogenesis

Background:

  • Prostate cancers often involve rearrangements fusing the TMPRSS2 promoter to the ERG gene, leading to ERG expression and promoting tumorigenesis.
  • ERG's role in prostate cancer is established, but the precise molecular mechanisms, particularly the requirement for ERK-mediated phosphorylation, remain unclear.
  • Targeting ERG is a potential therapeutic strategy, but requires a deeper understanding of its activation pathways.

Purpose of the Study:

  • To elucidate the molecular mechanism by which ERK-mediated phosphorylation of ERG drives prostate cancer progression.
  • To investigate the role of specific serine phosphorylation sites on ERG in regulating its transcriptional activity and cellular functions.
  • To identify potential therapeutic vulnerabilities in ERG-driven prostate cancers based on ERG phosphorylation.

Main Methods:

  • Investigated ERG phosphorylation using biochemical assays and identified specific serine residues targeted by ERK.
  • Utilized ChIP-seq to map the ERG cistrome and analyzed the impact of phosphorylation on ERG binding and target gene activation.
  • Assessed the effects of ERG phosphorylation on the recruitment of Polycomb Repressive Complex 2 (PRC2) components (EZH2, SUZ12) and cell migration.

Main Results:

  • Discovered a sequential phosphorylation mechanism: initial ERK phosphorylation induces a conformational change enabling subsequent phosphorylation at Ser-96.
  • Ser-96 phosphorylation of ERG leads to dissociation of EZH2/SUZ12, transcriptional activation of ERG target genes, and increased cell migration.
  • Loss of Ser-96 phosphorylation results in EZH2 recruitment across the ERG cistrome, inhibiting ERG-mediated transcription and cell migration.

Conclusions:

  • ERK-mediated phosphorylation of ERG, particularly at Ser-96, is a critical activation step that drives oncogenic functions in prostate cancer.
  • This phosphorylation event dictates the interaction of ERG with PRC2, influencing transcriptional output and cellular behavior.
  • The identified ERK-mediated ERG activation pathway presents a promising target for developing novel therapies for ERG-positive prostate cancers.
Keywords:
ETS transcription factor familymitogen-activated protein kinase (MAPK)polycombprostate cancertranscription factor

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