title: Altering cancer transcriptomes using epigenomic inhibitors.
abstract: BACKGROUND
  Due to the hyper-activation of WNT signaling in a variety of cancer types, there has been a strong drive to develop pathway-specific inhibitors with the eventual goal of providing a chemotherapeutic antagonist of WNT signaling to cancer patients. A new category of drugs, called epigenetic inhibitors, are being developed that hold high promise for inhibition of the WNT pathway. The canonical WNT signaling pathway initiates when WNT ligands bind to receptors, causing the nuclear localization of the co-activator β-catenin (CTNNB1), which leads to an association of β-catenin with a member of the TCF transcription factor family at regulatory regions of WNT-responsive genes. The TCF/β-catenin complex then recruits CBP (CREBBP) or p300 (EP300), leading to histone acetylation and gene activation. A current model in the field is that CBP-driven expression of WNT target genes supports proliferation whereas p300-driven expression of WNT target genes supports differentiation. The small molecule inhibitor ICG-001 binds to CBP, but not to p300, and competitively inhibits the interaction of CBP with β-catenin. Upon treatment of cancer cells, this should reduce expression of CBP-regulated transcription, leading to reduced tumorigenicity and enhanced differentiation.
  
  
  RESULTS
  We have compared the genome-wide effects on the transcriptome after treatment with ICG-001 (the specific CBP inhibitor) versus C646, a compound that competes with acetyl-coA for the Lys-coA binding pocket of both CBP and p300. We found that both drugs cause large-scale changes in the transcriptome of HCT116 colon cancer cells and PANC1 pancreatic cancer cells and reverse some tumor-specific changes in gene expression. Interestingly, although the epigenetic inhibitors affect cell cycle pathways in both the colon and pancreatic cancer cell lines, the WNT signaling pathway was affected only in the colon cancer cells. Notably, WNT target genes were similarly downregulated after treatment of HCT116 with C646 as with ICG-001.
  
  
  CONCLUSIONS
  Our results suggest that treatment with a general HAT inhibitor causes similar effects on the transcriptome as does treatment with a CBP-specific inhibitor and that epigenetic inhibition affects the WNT pathway in HCT116 cells and the cholesterol biosynthesis pathway in PANC1 cells.
authors.affiliation: USC/Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy Street, NRT 6503, Los Angeles, CA 90089-9601 USA.
authors.forename: Malaina
authors.initials: M
authors.lastname: Gaddis
authors.affiliation: School of Biological Sciences, University of Northern Colorado, Greeley, CO 80639 USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Gerrard
authors.affiliation: School of Biological Sciences, University of Northern Colorado, Greeley, CO 80639 USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.affiliation: USC/Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy Street, NRT 6503, Los Angeles, CA 90089-9601 USA.
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
keywords: C646; Cholesterol biosynthesis; Colon cancer; Epigenetic inhibitor; Histone acetylation; ICG-001; Pancreatic cancer; TCF7L2; WNT signaling