Abstract
Histone deacetylase (HDAC) inhibitor is known to have a cytotoxic effect on ovarian cancer cell lines. The present study analyzed the association between immunohistochemical HDAC expression and clinicopathological findings, in particular, the association with histological type and effect of chemotherapy. The histology of the 201 ovarian cancers addressed was as follows: Serous carcinoma (SEC), 100 cases; clear cell carcinoma (CCC), 56 cases; endometrioid carcinoma (EMC), 36 cases; and mucinous carcinoma (MUC), 9 cases. Immunohistochemical analyses of HDACs 1, 2, 3, 4, 5, 6 and 7 expression levels were performed using tissue microarrays, composed of 201 primary tumors and 38 tumors following chemotherapy. Overexpression of HDAC1 was detected in the nucleus of all cases with MUC, followed by CCC (80%), SEC (73%), and EMC (53%). CCC specifically demonstrated HDAC7 expression in both the nucleus (27%) and the cytoplasm (54%), and HDAC6 expression in the nucleus (34%). The comparison between prior to and following chemotherapy revealed a nuclear expression increase in HDAC1 (76% vs. 92%; P=0.03) and HDAC7 (0.0 vs. 16%; P=0.01), and cytoplasmic expression increase in HDAC6 (40 vs. 74%; P=<0.01) and HDAC7 (16 vs. 66%; P=<0.01). HDAC1 nuclear expression adversely affected overall survival in SEC (P=0.02) and EMC (P=0.03), and HDAC7 cytoplasmic expression in CCC was associated with a poor prognosis (P=0.06). In multivariate analysis, HDAC6 nuclear expression was determined as a poor prognostic factor (hazard ratio=3.51; 95% confidence interval, 1.49 to 8.27, P=<0.01). In the subgroup analysis, HDAC6 nuclear expression was associated with a poor prognosis in CCC (P=0.07), International Federation of Obstetrics and Gynecology stage III/IV (P=0.07), and suboptimal surgery (P=<0.01). In conclusion, HDACs may be associated with the prognosis of ovarian cancers, depending on the histological subtypes, and upregulated following chemotherapy. HDAC1, 6 and 7 may therefor act as promising therapeutic targets in the future.