Decreased acetylation of histone H3 in renal cell carcinoma: a potential target of histone deacetylase inhibitors.
OBJECTIVE
Recent studies suggest that alterations in chromatin structure by histone acetylation may have an important role in the neoplastic process. We evaluated histone H3 acetylation in renal cell carcinoma and the effects of a histone deacetylase inhibitor on renal cancer cell lines.


METHODS
The expression of acetylated histone H3 (Lys9) in renal cell carcinoma and corresponding nonneoplastic tissue specimens was evaluated. We next assessed immunohistologically the relationships between acetylated histone H3 expression and clinicopathological parameters in 44 cases of renal cell carcinoma. Furthermore, we evaluated the effects of the histone deacetylase inhibitor depsipeptide on the renal cancer cell lines Caki-1, ACHN, 769P and 786O (ATCC).


RESULTS
Acetylated histone H3 expression was decreased in 85.0% of renal cell carcinomas compared to levels in nonneoplastic tissue. Decreased expression was related to high nuclear tumor grade and advanced pathological tumor stage (p = 0.048 and 0.032, respectively). Depsipeptide inhibited cell line proliferation in a time and dose dependent manner. Depsipeptide induced apoptosis in Caki-1, ACHN and 786O, and induced G2 cell cycle arrest in 769P. Concomitantly depsipeptide increased acetylated histone H3 and p21(WAF/CIP1) expression, and induced Bcl-2 phosphorylation.


CONCLUSIONS
These results suggest that the decreased acetylation of histone H3 is a common alteration in a malignant phenotype of renal cell carcinoma. Increasing the amount of acetylated histone H3 might be a therapeutic option for renal cell carcinoma.
Kanao
Kent
K
Department of Urology, Keio University School of Medicine, Tokyo, Japan. cev14660@nyc.odn.ne.jp
Mikami
Shuji
S
Mizuno
Ryuichi
R
Shinojima
Toshiaki
T
Murai
Masaru
M
Oya
Mototsugu
M
D000107:Acetylation; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; D006655:Histone Deacetylases