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

Kumaravel Mohankumar, Rupesh Shrestha, Stephen Safe

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Paraspeckles compound 1 (PSPC1) is a multifunctional protein that plays an important role in cancer cells, where PSPC1 is a master regulator of pro-oncogenic responses that includes activation of TGFβ (TGFβ1), TGFβ-dependent EMT, and metastasis. The pro-oncogenic activities of PSPC1 closely resembled those observed for the orphan nuclear receptor 4A1 (NR4A1, Nur77) and knockdown of NR4A1 decreased expression of PSPC1 in MDA-MB-231 breast, H1299 lung, and SNU449 liver cancer cells. Similar results were observed in these same cell lines after treatment with bisindole–derived (CDIMs) NR4A1 antagonists. Moreover, PSPC1-dependent regulation of TGFβ, genes associated with cancer stem cells and epithelial to mesenchymal transition (EMT) were also downregulated after NR4A1 silencing or treatment of breast, lung, and liver cancer cells with CDIM/NR4A1 antagonists. Results of chromatin immunoprecipitation (ChIP) assays suggest that NR4A1 regulates PSPC1 through interaction with an NBRE sequence in the PSPC1 gene promoter. These results coupled with in vivo studies showing that NR4A1 antagonists inhibit breast tumor growth and downregulate PSPC1 in tumors indicate that the pro-oncogenic nuclear PSPC1 factor can be targeted by CDIM/NR4A1 antagonists.

Original languageEnglish (US)
Pages (from-to)73-84
Number of pages12
JournalMolecular Carcinogenesis
Issue number1
StatePublished - Jan 2022


  • NR4A1
  • Nur77
  • PSPC1
  • antagonists
  • ligands
  • Neoplasm Transplantation
  • Humans
  • Transforming Growth Factor beta1/metabolism
  • Methane/administration & dosage
  • RNA-Binding Proteins/genetics
  • Cell Survival/drug effects
  • Neoplastic Stem Cells/drug effects
  • Epithelial-Mesenchymal Transition/drug effects
  • Female
  • Cell Proliferation/drug effects
  • Breast Neoplasms/drug therapy
  • Promoter Regions, Genetic/drug effects
  • A549 Cells
  • PC-3 Cells
  • Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & inhibitors
  • HCT116 Cells
  • Hep G2 Cells
  • Xenograft Model Antitumor Assays
  • Animals
  • Cell Line, Tumor
  • Mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research


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