Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis.

Abstract

Beta-catenin accumulation is often found in lung tumors, but only a few patients have mutations in beta-catenin gene. In addition, activated p53 downregulates beta-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (beta-transducin repeat-containing protein) and p53 regulation could result in beta-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with beta-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P=0.023 approximately 0.041). Alteration of AXIN2 was associated with poor survival in early stage patients (P=0.016). Low expression of AXIN2 and betaTrCP was significantly associated with promoter hypermethylation and histone deacetylation. Ectopic expression and knockdown of p53, AXIN2 and betaTrCP genes in A549 (p53 wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of beta-catenin expression. Our clinical and cell model findings provide new evidence that epigenetic silencing of AXIN2/betaTrCP in the degradation complex and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the beta-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

• Authors: R-C Tseng, R-K Lin, C-K Wen, C Tseng, H-S Hsu, W-H Hsu, Y-C Wang
• Journal: Oncogene (Oncogene) Vol. 27 Issue 32 Pg. 4488-96 (Jul 24 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18372914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AXIN2 protein, human
• Axin Protein
• Cytoskeletal Proteins
• Hydroxamic Acids
• Tumor Suppressor Protein p53
• beta Catenin
• beta-Transducin Repeat-Containing Proteins
• Vorinostat
• Decitabine
• Azacitidine

Topics

• Active Transport, Cell Nucleus
• Axin Protein
• Azacitidine (analogs & derivatives, pharmacology)
• Carcinoma, Non-Small-Cell Lung (etiology, genetics, metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoskeletal Proteins (genetics, physiology)
• DNA Methylation
• Decitabine
• Epigenesis, Genetic
• Gene Silencing
• Humans
• Hydroxamic Acids (pharmacology)
• Lung Neoplasms (etiology, genetics, metabolism)
• Prognosis
• Promoter Regions, Genetic
• Tumor Suppressor Protein p53 (physiology)
• Vorinostat
• beta Catenin (metabolism)
• beta-Transducin Repeat-Containing Proteins (genetics, physiology)