Open AccessHBP 1 promoter methylation augments the oncogenic β‐catenin to correlate with prognosis in NSCLC
Author(s) -
Tseng RuoChia,
Huang WayRen,
Lin SuFeng,
Wu PeiChen,
Hsu HanShui,
Wang YiChing
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12318
Subject(s) - transactivation , cancer research , dna methylation , lung cancer , catenin , biology , gene silencing , immunohistochemistry , ectopic expression , gene knockdown , transcription factor , gene expression , medicine , gene , wnt signaling pathway , pathology , immunology , biochemistry
β‐catenin nuclear accumulation is frequently identified in human non‐small cell lung cancer ( NSCLC ). The HMG ‐box transcription factor 1 ( HBP 1) is a known repressor of β‐catenin transactivation. However, the role of HBP 1 in relation to β‐catenin nuclear accumulation has not been addressed in human cancer patients. In addition, the mechanism of HBP 1 gene alteration in NSCLC remains unclear, although HBP 1 mutation and gene deletion of HBP 1 are reported in breast and colon cancers. Here, we demonstrate that HBP 1 acts as a tumour suppressor and serves as a prognostic biomarker in NSCLC clinical and cell models. The immunohistochemistry data indicated that 30.5% (25/82) of tumours from NSCLC patients showed absence or low expression of HBP 1 protein. A significant inverse correlation between m RNA /protein expression and promoter hypermethylation suggested that promoter hypermethylation is responsible for low expression of HBP 1 in NSCLC patients. Reactivation of HBP 1 expression by demethylation reagent or ectopic expression of HBP 1 suppressed β‐catenin transactivation. Conversely, HBP 1 knockdown increased β‐catenin transactivation. Importantly, preserved expression of HBP 1 had a significantly protective effect on prognosis in patients with β‐catenin nuclear accumulation, suggesting that low expression of HBP 1 in NSCLC patients with β‐catenin nuclear accumulation was one of the major determinants of prognosis. Our data from cellular and clinical models suggest that HBP 1 is a suppressor of cancer progression, making it a potential prognostic predictor and therapeutic target to attenuate lung cancer progression.