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Nuclear receptor 4A1 (NR4A1) antagonists target paraspeckle component 1 (PSPC1) in cancer cells

Kumaravel Mohankumar1, Rupesh Shrestha2, Stephen Safe1

  • 1Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.

Molecular Carcinogenesis
|October 26, 2021
PubMed

Insights

The orphan nuclear receptor 4A1 (NR4A1) antagonist bisindole derivatives (CDIMs) downregulate the pro-oncogenic protein Paraspeckles compound 1 (PSPC1). This suggests NR4A1 antagonists can target PSPC1 in cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Paraspeckles compound 1 (PSPC1) is a key regulator of pro-oncogenic pathways, including TGFβ signaling, epithelial-mesenchymal transition (EMT), and metastasis.
  • The orphan nuclear receptor 4A1 (NR4A1, Nur77) exhibits pro-oncogenic activities similar to PSPC1.
  • NR4A1 and PSPC1 expression are interdependent in various cancer cell lines.

Purpose of the Study:

  • To investigate the regulatory relationship between NR4A1 and PSPC1 in cancer cells.
  • To evaluate the efficacy of NR4A1 antagonists in targeting PSPC1-mediated oncogenic pathways.
  • To elucidate the mechanism by which NR4A1 regulates PSPC1 expression.

Main Methods:

  • Silencing of NR4A1 in breast, lung, and liver cancer cell lines.
  • Treatment of cancer cells with bisindole-derived (CDIMs) NR4A1 antagonists.
  • Chromatin immunoprecipitation (ChIP) assays to assess NR4A1 binding to the PSPC1 promoter.
  • In vivo studies using mouse models of breast cancer.

Main Results:

  • NR4A1 knockdown or treatment with CDIMs significantly downregulated PSPC1 expression in multiple cancer cell lines.
  • NR4A1 silencing or CDIM treatment reduced TGFβ signaling, EMT markers, and cancer stem cell-associated genes.
  • ChIP assays indicated that NR4A1 directly binds to an NBRE sequence in the PSPC1 gene promoter.
  • In vivo studies demonstrated that NR4A1 antagonists inhibit breast tumor growth and decrease PSPC1 levels in tumors.

Conclusions:

  • NR4A1 plays a crucial role in regulating PSPC1 expression and its downstream oncogenic functions.
  • Bisindole-derived NR4A1 antagonists effectively inhibit PSPC1-mediated pro-oncogenic pathways.
  • Targeting NR4A1 with CDIMs represents a potential therapeutic strategy for cancers driven by PSPC1.
Keywords:
NR4A1Nur77PSPC1antagonistsligands

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