Reduced Acetylated Histone H4 is Associated With Promoter Methylation of the Fragile Histidine Triad Gene in Resected Esophageal Squamous Cell Carcinoma

Abstract

Promoter methylation inactivates expression of some important tumor suppressor genes and may be associated with histone modification. The fragile histidine triad (FHIT) gene is considered a tumor suppressor gene in different human epithelial cancers. We investigated whether FHIT methylation is associated with aberrant expression of Fhit protein and acetylated histone, and whether aberrant expression of Fhit protein and acetylated histone are related to prognosis after resection for esophageal squamous cell cancer. We analyzed FHIT methylation using methylation-specific polymerase chain reaction and Fhit protein and acetylated histone H4 using immunohistochemistry in 60 resected tumor specimens. Concordance analysis was performed between FHIT methylation and expression of Fhit as well as H4. The FHIT methylation was observed in 33(55%) specimens, and the aberrant expression of Fhit and acetylated H4 was found in 42 (70%) and 40 (67%) specimens, respectively. Expression of aberrant Fhit correlated positively with tumor staging (p < 0.017) and nodal involvement (p = 0.004). Aberrant expression of acetylated H4 correlated positively with tumor staging (p < 0.001), nodal involvement (p < 0.001), and metastasis (p = 0.004). Concordance rates of 75% and 81.7% were present between promoter methylation of FHIT and expression of Fhit (p = 0.035) and acetylated H4 (p = 0.02). Aberrant expression of Fhit and acetylated histone H4 are frequently associated with the presence of esophageal squamous cell carcinoma, and they are potential prognostic predictors for patients after resection of the tumor.