Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells.
Overexpression of histone deacetylases has been reported in various human malignancies; however, the expression of histone deacetylases in endometrial tissue is not fully understood. In the present study, the expression of histone deacetylase 1, histone deacetylase 2, and Ki-67 was examined immunohistochemically in 30 normal and 66 malignant endometrial tissue samples. The results were expressed as a positivity index and compared with the positivity index for Ki-67 and rates of patient survival. The effect of 2 histone deacetylase inhibitors, trichostatin A and apicidine, on cell proliferation and the expression of cell cycle regulators such as cyclins (D1, E, and A), p21, p27, and p16 were investigated using 6 endometrial carcinoma cell lines. The positivity index for histone deacetylase 1 (79.8 +/- 33.0, mean +/- SD) and histone deacetylase 2 (106.3 +/- 41.9) was higher in endometrial carcinoma than the normal endometrium, with a significant difference for histone deacetylase 2. The positivity index for histone deacetylase 2 was significantly increased in higher-grade carcinomas (positivity index for grade 3, 124.9 +/- 28.4) compared with grade 1 tumors (86.0 +/- 41.0) and was positively correlated with that for Ki-67. In addition, patients with histone deacetylase 2-positive carcinomas had a poor prognosis compared with those with histone deacetylase 2-negative carcinoma (P = .048). Treatment with trichostatin A or apicidine suppressed the proliferation in all cell lines examined, in association with increased expression of p21 and down-regulation of cyclin D1 and cyclin A expression. These results indicated that increased histone deacetylase 2 expression is involved in the acquisition of aggressive behavior by endometrial carcinoma and suggest histone deacetylase inhibitor to be a promising anticancer drug for this carcinoma.
Fakhry
Hussein
H
Surgical Oncology Department, South Egypt Cancer Institute Assiut University, Assiut 7111, Egypt.
Miyamoto
Tsutomu
T
Kashima
Hiroyasu
H
Suzuki
Akihisa
A
Ke
He
H
Konishi
Ikuo
I
Shiozawa
Tanri
T
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D004717:Endometrium / Q000201:enzymology / Q000473:pathology; D005260:Female; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000494:pharmacology; D011379:Prognosis; D016019:Survival Analysis
D018797:Cell Cycle Proteins; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; D010456:Peptides, Cyclic; C102351:apicidin; C012589:trichostatin A; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2