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β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells

Abstract

Background Cyclooxygenase-2 (COX-2) overexpression in colorectal cancer increases levels of its pro-tumorigenic product prostaglandin E2 (PGE2). The recently identified colorectal tumour suppressor 15-prostaglandin dehydrogenase (15-PGDH) catalyses prostaglandin turnover and is downregulated at a very early stage in colorectal tumorigenesis; however, the mechanism responsible remains unclear. As Wnt/β-catenin signalling is also deregulated early in colorectal neoplasia, a study was undertaken to determine whether β-catenin represses 15-PGDH expression.

Methods The effect of modulating Wnt/β-catenin signalling (using β-catenin siRNA, mutant TCF4, Wnt3A or GSK3 inhibition) on 15-PGDH mRNA, protein expression and promoter activity was determined in colorectal cell lines by immunoblotting, qRT-PCR and reporter assays. The effect of β-catenin deletion in vivo was addressed by 15-PGDH immunostaining of β-catenin−/lox-villin-creERT2 mouse tissue. 15-PGDH promoter occupancy was determined using chromatin immunoprecipitation and PGE2 levels by ELISA.

Results The study shows for the first time that β-catenin knockdown upregulates 15-PGDH in colorectal adenoma and carcinoma cells without affecting COX-2 protein levels. A dominant negative mutant form of TCF4 (dnTCF4), unable to bind β-catenin, also upregulated 15-PGDH; conversely, increasing β-catenin activity using Wnt3A or GSK3 inhibition downregulated 15-PGDH. Importantly, inducible β-catenin deletion in vivo also upregulated intestinal epithelial 15-PGDH. 15-PGDH regulation occurred at the protein, mRNA and promoter activity levels and chromatin immunoprecipitation indicated β-catenin/TCF4 binding to the 15-PGDH promoter. β-catenin knockdown decreased PGE2 levels, and this was significantly rescued by 15-PGDH siRNA.

Conclusion These data suggest a novel role for β-catenin in promoting colorectal tumorigenesis through very early 15-PGDH suppression leading to increased PGE2 levels, possibly even before COX-2 upregulation.

  • 15-PGDH
  • β-catenin
  • PGE2
  • cyclooxygenase
  • colorectal cancer prevention
  • colorectal neoplasia
  • prostaglandins
  • cell biology
  • colon carcinogenesis
  • intestinal epithelium
  • gastrointestinal peptides
  • inflammatory bowel disease
  • cancer genetics
  • colorectal cancer
  • colorectal cancer genes
  • colorectal carcinoma
  • colorectal neoplasm
  • gene regulation
  • cell biology
  • cell death
  • cancer prevention
  • chemoprevention
  • cyclooxygenase-2
  • dietary fibre
  • butyrate

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