Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in lung tumorigenesis.
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.
Tseng
R-C
RC
Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan, ROC.
Lin
R-K
RK
Wen
C-K
CK
Tseng
C
C
Hsu
H-S
HS
Hsu
W-H
WH
Wang
Y-C
YC
D021581:Active Transport, Cell Nucleus; D060466:Axin Protein; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000502:physiology; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000077337:Vorinostat; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics* / Q000502:physiology
C491761:AXIN2 protein, human; D060466:Axin Protein; D003598:Cytoskeletal Proteins; D006877:Hydroxamic Acids; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000077337:Vorinostat; D000077209:Decitabine; D001374:Azacitidine