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

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 pro-oncogenic 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.

• Authors: Stephen Safe, Rupesh Shrestha, Kumaravel Mohankumar, Marcell Howard, Erik Hedrick, Maen Abdelrahim
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 27 Issue 38 Pg. 6387-6398 (Oct 14 2021) ISSN: 2219-2840 [Electronic] United States
• PMID: 34720529 (Publication Type: Journal Article, Review)
• Copyright: ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.

Chemical References

• Receptors, Cytoplasmic and Nuclear
• Sp Transcription Factors
• Transcription Factors

Topics

• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Oncogenes
• Pancreatic Neoplasms (drug therapy, genetics)
• Receptors, Cytoplasmic and Nuclear (genetics)
• Sp Transcription Factors (genetics, metabolism)
• Transcription Factors (genetics)