Epigenetic Modulation of Tumor Suppressor CCAAT/Enhancer Binding Protein α Activity in Lung Cancer

Abstract

DNA hypermethylation of the upstream C/EBPalpha promoter region, not the core promoter region as previously reported, is critical in the regulation of C/EBPalpha expression in human lung cancer.

Immunohistochemical analysis of C/EBPα in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: A correlative study of E3590

“…Tada et al demonstrated the epigenetic modulation of this gene in lung cancer (30). Both in lung cancer cell lines and in patients' tumors presence of upstream promoter methylation was significantly correlated with lack of C/EBPα RNA levels (30). In the pathologic specimens studied, there was a statistically significant inverse correlation between the density of methylation and loss of C/ EBPα using an IHC method similar to ours (30).…”

“…These results identified C/EBPα as a master regulator of airway epithelial maturation and suggested that the loss of this gene could be an important event in the multistep process of lung carcinogenesis. Furthermore, our group (29) and others (30) have previously identified down-regulation of C/EBPα in a large proportion of lung cancer cell lines and primary tumor samples.…”

“…We have shown that C/EBPα mutations are a rare event in lung cancer (only 1 sequence change in 50 primary NSCLC tumor DNA samples analyzed) (35). Tada et al demonstrated the epigenetic modulation of this gene in lung cancer (30). Both in lung cancer cell lines and in patients' tumors presence of upstream promoter methylation was significantly correlated with lack of C/EBPα RNA levels (30).…”

“…Tada and colleagues also showed the frequent down-regulation of C/EBPα in NSCLC and identified methylation of the upstream promoter of this gene as the mechanism of silencing. Loss of C/ EBPα is one of the most common genetic events in NSCLC and therefore supports C/EBPα as a critical tumor suppressor gene in lung cancer (30).…”

“…Both in lung cancer cell lines and in patients' tumors presence of upstream promoter methylation was significantly correlated with lack of C/EBPα RNA levels (30). In the pathologic specimens studied, there was a statistically significant inverse correlation between the density of methylation and loss of C/ EBPα using an IHC method similar to ours (30). These data establish IHC as a possible surrogate marker of C/EBPα upstream promoter methylation in NSCLC and validate the use of an IHC method as a marker of C/EBPα expression.…”