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Nucleolin represses transcription of the androgen receptor gene through a G-quadruplex

Cindy K Miranti1,2, Sara Moore3, Yongeun Kim4

  • 1University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.

Oncotarget
|June 2, 2020
PubMed

Insights

Nuclear nucleolin (NCL) suppresses androgen receptor (AR) expression by binding to a G-quadruplex (G4) in the AR promoter. G4-stabilizing compounds, with NCL, selectively kill prostate cancer cells, offering new CRPC treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Androgen receptor (AR) signaling drives prostate cancer, but resistance to androgen-deprivation therapies (ADT) leads to castration-resistant prostate cancer (CRPC).
  • Current ADT strategies involve AR antagonists and androgen synthesis inhibitors, yet resistance often arises from AR signaling maintained by ligand-independent mechanisms.
  • Novel therapeutic approaches are crucial to overcome CRPC by effectively blocking AR signaling.

Purpose of the Study:

  • To investigate the role of the nuclear scaffold protein nucleolin (NCL) in regulating AR expression.
  • To explore the potential of G-quadruplex (G4) structures and stabilizing compounds as a therapeutic strategy against AR-driven prostate cancer.

Main Methods:

  • Assessed NCL's interaction with the AR promoter using G-quadruplex (G4) binding assays.
  • Investigated the effect of NCL binding on AR gene expression in AR-expressing tumor cells.
  • Evaluated the efficacy of a novel G4 compound in suppressing AR expression and inducing cell death in CRPC models.

Main Results:

  • Demonstrated that nucleolin (NCL) directly suppresses androgen receptor (AR) expression by binding to a G-quadruplex (G4) structure in the AR promoter.
  • Confirmed that NCL's binding to the AR promoter's G4-element is essential for suppressing AR expression in AR-positive tumor cells.
  • Showed that G4-stabilizing compounds, in conjunction with NCL, effectively decrease AR expression and selectively kill AR-expressing cancer cells, including CRPC lines.

Conclusions:

  • Nucleolin (NCL) acts as a transcriptional repressor of the androgen receptor (AR) via G-quadruplex (G4) interactions.
  • G4-stabilizing drugs represent a promising therapeutic avenue for CRPC by enhancing NCL's ability to suppress AR expression.
  • Targeting the NCL-G4-AR interaction could provide a novel strategy to overcome resistance in advanced prostate cancer.
Keywords:
G-quadruplexandrogen receptorgene repressionnucleolinprostate cancer

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