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

Oncogene volume 27, pages 4488–4496 (2008)Cite this article

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.

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Abbreviations

NSCLC:

non-small cell lung cancer

RT–PCR:

reverse transcriptase–PCR

MSP:

methylation-specific PCR

LOH:

loss of heterozygosity

5-aza-dC:

5-aza-2′-deoxycytidine

SAHA:

suberoylanilide hydroxamic acid

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Acknowledgements

This research was funded in part by Grants NSC95-2320-B-006-087-MY3 and DOH97-TD-G-111-004 from the National Science Council (The Executive Yuan, ROC).

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Authors and Affiliations

  1. Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC

    R-C Tseng, R-K Lin, C-K Wen & Y-C Wang

  2. Department of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan, ROC

    C Tseng

  3. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan, ROC

    H-S Hsu & W-H Hsu

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  1. R-C Tseng
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Corresponding author

Correspondence to Y-C Wang.

Additional information

Originality: Our data provide new evidences for β-catenin accumulation through inactivation of AXIN2/betaTrCP-mediated stability control and blockage of p53-promoted β-catenin degradation in lung cancer. This is also the first study to show that AXIN2 and betaTrCP augment the p53 downregulation of β-catenin expression. Promoter hypermethylation and histone deacetylation are the predominant mechanisms of AXIN2 and betaTrCP inactivation in lung cancer.

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Tseng, RC., Lin, RK., Wen, CK. et al. Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis. Oncogene 27, 4488–4496 (2008). https://doi.org/10.1038/onc.2008.83

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