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

R. C. Tseng, R. K. Lin, C. K. Wen, C. Tseng, H. S. Hsu, W. H. Hsu, Y. C. Wang

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

β-catenin accumulation is often found in lung tumors, but only a few patients have mutations in β-catenin gene. In addition, activated p53 downregulates β-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (β-transducin repeat-containing protein) and p53 regulation could result in β-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with β-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P=0.023∼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 β-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 β-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the β-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

Original languageEnglish
Pages (from-to)4488-4496
Number of pages9
JournalOncogene
Volume27
Issue number32
DOIs
Publication statusPublished - Jul 24 2008
Externally publishedYes

Fingerprint

beta-Transducin Repeat-Containing Proteins
Catenins
Epigenomics
Carcinogenesis
Lung
Proteins
Lung Neoplasms
Down-Regulation
Transducin
Non-Small Cell Lung Carcinoma
Histones
Genes

Keywords

  • β-catenin
  • AXIN2
  • BetaTrCP
  • Epigenetic alteration
  • NSCLC
  • P53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis. / Tseng, R. C.; Lin, R. K.; Wen, C. K.; Tseng, C.; Hsu, H. S.; Hsu, W. H.; Wang, Y. C.

In: Oncogene, Vol. 27, No. 32, 24.07.2008, p. 4488-4496.

Research output: Contribution to journalArticle

Tseng, R. C. ; Lin, R. K. ; Wen, C. K. ; Tseng, C. ; Hsu, H. S. ; Hsu, W. H. ; Wang, Y. C. / Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis. In: Oncogene. 2008 ; Vol. 27, No. 32. pp. 4488-4496.
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