Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.Epithelial ovarian carcinoma, which comprises the majority of malignant ovarian tumors, is the leading cause of death related to gynecological malignancies in women. 1 The survival rate of ovarian carcinoma patients has not improved significantly for years, and further understanding of the biology of ovarian carcinoma cells is critical for the development of new treatments. 2 Several studies have reported that the poor prognosis of ovarian carcinoma is related not only to the high proliferative activity of carcinoma cells, 3-6 but also to metastasis. 7-9 One important event in metastasis is the loss of adhesion between tumor cells caused by a downregulation of E-cadherin expression, which has been reported to occur via genetic or epigenetic changes. [10][11][12] Histone acetylation/deacetylation controls chromatin activity. The acetylation of histones is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups on the NH2-terminal lysine residues of core nucleosomal histones and this activity is generally associated with transcriptional repression of tumor suppressors, such as p21 and E-cadherin. Through these mechanisms, HDACs act as critical regulators of cell growth, differentiation and apoptotic programs. The famil...

Hypoxia is known to play important roles in the development and progression of tumors. We previously demonstrated that S100A4, a critical molecule for metastasis, was upregulated in ovarian cancer cells. Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the increased binding of HIF-1a to a methylation-free HRE in ovarian carcinoma cells. These results indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the ''metastatic phenotype.''The metastatic potential of tumor cells has been reported to be regulated by their interactions with their microenvironment. These interactions can be modified by the accumulation of genetic and epigenetic changes, which are transient alterations induced by the local tumor microenvironment. In particular, the role of microenvironmental hypoxia has been focused on with regard to tumorigenesis, tumor progression and tumor biology. [1][2][3][4] Hypoxia is known to induce the expression of the transcription factor hypoxia-inducible factor (HIF), which has been reported to be upregulated in human malignancy. 5 HIF binds to hypoxia-response elements (HRE) 3 and activates the transcription of various target genes, not only angiogenetic factors but also metastasisassociated genes. 6 We previously reported that hypoxia was associated with invasive phenotypes in ovarian carcinomas. 7,8 In addition, HIF-1a overexpression is associated with a poor prognosis in patients with ovarian cancer, 9 suggesting that hypoxia is important for the acquisition of aggressive behavior in ovarian cancer cells. S100A4, which is also known as mts-l/metastasin/pEL98/ p9k, 10,11 belongs to the calcium binding S100 protein family. Altered expression levels of S100 proteins have been reported in several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions and are associated with cell motility and invasion. 11 Interestingly, a recent report suggested that cancer cells induce S100 expression to produce an appropriate metastatic site via an autocrine/paracrine pathway 12,13 and that S100A4 might be a cancer stem cell (CSC) marker. 14 We also reported that S100A4 expression was upregulated in ovarian cancer and that the expression of S100A4 was an independent pro...

Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.

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