Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas.
Metastasis-associated protein MTA1 and histone deacetylase form a protein complex with histone deacetylase activity that plays an important role in histone deacetylation, alteration of chromatin structure and transcriptional control. The precise role of the MTA1 protein in the malignant progression of human cancers remains unknown, however, especially its overexpression and relationship with histone acetylation/deacetylation in experimental and clinical tumors. The expression levels of MTA1 protein and the acetylation levels of histone H4 were examined in 70 cases of surgically resected esophageal squamous cell carcinomas, using immunohistochemistry. The intensities of immunostaining of MTA1 protein and acetylated histone H4 in carcinoma tissues (Ca) were compared to normal epithelium (N) contained in the same section. Thirty of 70 cases (42.9%) displayed overexpression of MTA1 protein (N < Ca). Cancers overexpressing MTA1 protein invaded deeper into the esophageal wall (p < 0.005) and showed significantly higher degrees of lymph node metastasis (p < 0.01), higher pathological stage, more lymphatic involvement and poorer prognosis (p < 0.05) than the remaining cases. The acetylation levels of histone H4 inversely correlated to the depth of cancer invasion and pathological stage (p < 0.05), and the patients with higher level of histone H4 acetylation had a better prognosis (p < 0.05). Furthermore, immunostaining patterns of MTA1 and acetylated histone H4 were inversely correlated (p < 0.001), demonstrating the relationship of deacetylation of histone H4 in MTA1-overexpressing carcinomas. In conclusion, the data suggest that the overexpression of MTA1 protein and acetylation level of histone H4 protein, both of which are closely related, might be useful predictors of malignant potential of esophageal squamous cell carcinomas. Thus, strategies involving inhibition of MTA1 function as well as inhibition of histone deacetylation could be novel approaches for the treatment of esophageal squamous cell carcinomas.
Toh
Yasushi
Y
Department of Gastroenterological Surgery, National Kyushu Cancer Center, Fukuoka, Japan. ytoh@nk-cc.go.jp
Ohga
Takefumi
T
Endo
Kazuya
K
Adachi
Eisuke
E
Kusumoto
Hiroki
H
Haraguchi
Masaru
M
Okamura
Takeshi
T
Nicolson
Garth L
GL
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism*; D004947:Esophagus / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D009092:Mucous Membrane / Q000473:pathology; D011379:Prognosis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases