Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells

Fakhry, Hussein; Miyamoto, Tsutomu; Kashima, Hiroyasu; Suzuki, Akihisa; Ke, He; Konishi, Ikuo; Shiozawa, Tanri

doi:10.1016/j.humpath.2009.11.012

« Previous Next »Human Pathology
Volume 41, Issue 6 , Pages 848-858, June 2010

Immunohistochemical detection of histone deacetylases in endometrial carcinoma: involvement of histone deacetylase 2 in the proliferation of endometrial carcinoma cells

Hussein Fakhry, MD
- Surgical Oncology Department, South Egypt Cancer Institute Assiut University, Assiut 7111, Egypt
Tsutomu Miyamoto, MD, PhD
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Hiroyasu Kashima, MD
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Akihisa Suzuki, MD
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
He Ke, MD
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
Ikuo Konishi, MD, PhD
- Department of Gynecology and Obstetrics, Kyoto University Faculty of Medicine, Kyoto 606-8527, Japan
Tanri Shiozawa, MD, PhD
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Corresponding author. Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.

Received 30 May 2009; received in revised form 18 November 2009; accepted 20 November 2009. published online 24 February 2010.

Summary

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.

Keywords: Endometrial carcinoma, HDAC, Prognosis, Immunohistochemistry