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Review
. 2021 Oct 14;27(38):6387-6398.
doi: 10.3748/wjg.v27.i38.6387.

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

Stephen Safe  1 , Rupesh Shrestha  2 , Kumaravel Mohankumar  3 , Marcell Howard  3 , Erik Hedrick  4 , Maen Abdelrahim  5
Affiliations
Review

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

Stephen Safe et al. World J Gastroenterol. .

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.

Keywords: Ligand inhibitors; Nuclear receptor 4A antagonists; Nuclear receptor 4A1; Pancreatic cancer; Specificity protein; Transcription factors.

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Conflict of interest statement

Conflict-of-interest statement: Authors declare no conflict of interests for this article.

Figures

Figure 1
Figure 1
Common functional properties of specificity protein transcription factors and nuclear receptor 4A1 in pancreatic and other cancer cells. Specificity protein (Sp) transcription factors (TFs) (Sp1, Sp3 and Sp4) bind GC-rich gene promoter sequences to activate gene expression associated with enhanced cell proliferation, survival, migration, invasion and metastasis. Nuclear receptor 4A1 (NR4A1) binds as monomer or homodimers to NBRE and NuRE promoter elements and NR4A1 also acts as a cofactor for Sp1 and Sp4-regulated genes and NR4A1/Sp binds GC-rich promoter sequences. Sp: Specificity protein; TFs: Transcription factors; NR4A1: Nuclear receptor 4A1.
Figure 2
Figure 2
Genomic analysis of Sp1, Sp3 and Sp4 regulated genes in pancreatic cancer cells. A: The number of total genes regulated by specificity protein (Sp) transcription factors (TFs) in Panc1 cell was determined by individual Sp knockdown (siSp1, siSp3 and siSp4) and the number of unique (Different genes) and commonly repressed (Genes commonly repressed) and induced (Genes commonly induced) genes are indicated; B-D: Ingenuity Pathway Analysis analysis of genes that regulate cell proliferation (B), cell death (C) and migration/invasion (D) compares the number of unique and commonly repressed/induced genes by Sp1 and Sp3, Sp1 and Sp4 and Sp3 and Sp4 as described[66].
Figure 3
Figure 3
Structures of agents that target downregulation of Sp1, Sp3 and Sp4 in pancreatic and other cancer cell lines[68]. The structurally diverse compounds act through multiple pathways in different cancer cell lines.
Figure 4
Figure 4
Mechanism of reactive oxygen species-dependent downregulation of specificity protein transcription factors. Induction of reactive oxygen species results in epigenetic suppression of Myc, downregulation of microRNAs, induction of ZBTB suppressors and decreased expression of specificity protein (Sp) transcription factors and Sp-regulated genes[20]. ROS: Reactive oxygen species; Sp: Specificity protein.
Figure 5
Figure 5
Nuclear receptor 4A1 ligands. Structures of compounds that directly bind nuclear receptor 4A1 include DIM-C-pPhOH, IMCA, cytosporone B and celastrol[76-80].
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