Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer

Stephen Safe, Kumaravel Mohankumar, Marcell Howard, Rupesh Shrestha, Erik Hedrick, Maen Abdelrahim

Research output: Contribution to journalReview articlepeer-review

Abstract

Specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4, and the orphan nuclear receptor 4A1 (NR4A1) are highly expressed in pancreatic tumors and Sp1 is a negative prognostic factor for pancreatic cancer patient survival. Results of knockdown and overexpression of Sp1, Sp3 and Sp4 in pancreatic and other cancer lines show that these TFs are individually pro-oncogenic factors and loss of one Sp TF is not compensated by other members. NR4A1 is also a prooncogenic factor and both NR4A1 and Sp TFs exhibit similar functions in pancreatic cancer cells and regulate cell growth, survival, migration and invasion. There is also evidence that Sp TFs and NR4A1 regulate some of the same genes including survivin, epidermal growth factor receptor, PAX3-FOXO1, α5- and α6- integrins, β1-, β3- and β4-integrins; this is due to NR4A1 acting as a cofactor and mediating NR4A1/Sp1/4-regulated gene expression through GC-rich gene promoter sites. Several studies show that drugs targeting Sp downregulation or NR4A1 antagonists are highly effective inhibitors of Sp/NR4A1-regulated pathways and genes in pancreatic and other cancer cells, and the triterpenoid celastrol is a novel dual-acting agent that targets both Sp TFs and NR4A1.

Original languageEnglish (US)
Pages (from-to)6387-6398
Number of pages12
JournalWorld Journal of Gastroenterology
Volume27
Issue number38
DOIs
StatePublished - Oct 14 2021

Keywords

  • Ligand inhibitors
  • Nuclear receptor 4A antagonists
  • Nuclear receptor 4A1
  • Pancreatic cancer
  • Specificity protein
  • Transcription factors

ASJC Scopus subject areas

  • Gastroenterology

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