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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
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PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

Lorea Valcarcel-Jimenez1, Alice Macchia1, Eva Crosas-Molist2,3

  • 1CIC bioGUNE, Bizkaia, Spain.

Cancer Research
|October 10, 2019
PubMed

Insights

Prostate tumor suppressor PGC1α, when partnered with ERRα, inhibits prostate cancer cell migration and invasion. This complex suppresses aggressive tumor properties by regulating MYC levels and cytoskeletal organization.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Prostate tumor suppressor PPARγ coactivator 1 alpha (PGC1α) regulates cellular metabolism.
  • Downregulation of PGC1α in prostate cancer correlates with increased metastasis.
  • The role of PGC1α in controlling prostate cancer cell aggressiveness requires further elucidation.

Purpose of the Study:

  • To investigate the function of the PGC1α-ERRα transcriptional complex in prostate cancer.
  • To determine the mechanisms by which PGC1α influences prostate cancer cell invasion and migration.
  • To explore the relationship between PGC1α-ERRα activity and MYC in prostate cancer.

Main Methods:

  • Cell culture of prostate cancer lines.
  • CRISPR/Cas9 gene editing to delete ERRα.
  • Assessment of cell migration, invasion, and cytoskeletal remodeling in vitro and in vivo.
  • Analysis of integrin alpha 1, beta 4, and MYC expression and activity.
  • Chromatin immunoprecipitation to assess PGC1α-ERRα binding at the MYC promoter.

Main Results:

  • PGC1α expression significantly reduced prostate cancer cell migration and invasion.
  • This effect was associated with cytoskeletal remodeling and decreased integrin alpha 1 and beta 4 expression.
  • CRISPR/Cas9-mediated deletion of ERRα abolished PGC1α's inhibitory effects on invasiveness.
  • PGC1α suppressed MYC levels and activity, with PGC1α and ERRα binding to the MYC promoter.
  • Inverse correlation between PGC1α-ERRα activity and MYC levels observed in patient data.

Conclusions:

  • The PGC1α-ERRα complex acts as a tumor suppressor in prostate cancer.
  • This complex inhibits cancer cell aggressiveness by regulating cytoskeletal organization and MYC signaling.
  • Downregulation of PGC1α-ERRα contributes to prostate cancer metastasis.

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