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

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 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 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 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 Nuclear receptor 4A1 ligands. Structures of compounds that directly bind nuclear receptor 4A1 include DIM-C-pPhOH, IMCA, cytosporone B and celastrol[76-80].