Safe S, Shrestha R, Mohankumar K, Howard M, Hedrick E, Abdelrahim M. Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer. World J Gastroenterol 2021; 27(38): 6387-6398 [PMID: 34720529 DOI: 10.3748/wjg.v27.i38.6387]
Corresponding Author of This Article
Stephen Safe, PhD, Full Professor, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77845, United States. ssafe@cvm.tamu.edu
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Oct 14, 2021; 27(38): 6387-6398 Published online Oct 14, 2021. doi: 10.3748/wjg.v27.i38.6387
Transcription factors specificity protein and nuclear receptor 4A1 in pancreatic cancer
Stephen Safe, Rupesh Shrestha, Kumaravel Mohankumar, Marcell Howard, Erik Hedrick, Maen Abdelrahim
Stephen Safe, Kumaravel Mohankumar, Marcell Howard, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77845, United States
Rupesh Shrestha, Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77845, United States
Erik Hedrick, Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, United States
Maen Abdelrahim, Department of Medical Oncology, Houston Methodist Hospital Cancer Center, Houston, TX 77030, United States
Author contributions: Safe S, Abdelrahim M and Hedrick E substantial contributions to conception and design of the study, acquisition of data, or analysis and interpretation of data; Shrestha R and Howard M drafting the article or making critical revisions related to important intellectual content of the manuscript; Safe S, Mohankumar K and Shrestha R final approval of the version of the article to be published.
Supported byHouston Methodist Cancer Center Innovation Award.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Stephen Safe, PhD, Full Professor, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77845, United States. ssafe@cvm.tamu.edu
Received: January 14, 2021 Peer-review started: January 14, 2021 First decision: March 29, 2021 Revised: April 30, 2021 Accepted: September 6, 2021 Article in press: September 6, 2021 Published online: October 14, 2021
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.
Core Tip: Specificity protein (Sp), transcription factors (TFs), Sp1, Sp3 and Sp4, and nuclear receptor 4A1 (NR4A1, Nur77) are highly expressed in pancreatic cancer cells and tumors. Results of gene silencing studies show that Sp TFs and NR4A1 are pro-oncogenic and regulate pathways/genes associated with cell proliferation, survival and migration/invasion. Bis-indole derived ligands (CDIMs) that bind NR4A1 act as NR4A1 antagonists and we discuss an important mechanism of gene regulation by NR4A1/Sp complexes which can be inhibited by NR4A1 antagonists.
