The anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) on the aggressive phenotypes of ovarian carcinoma cells.
Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been shown to act selectively on gene expression, and are potent inducers of growth arrest, differentiation and apoptosis in various types of cancers in vitro and in vivo. This study aimed to elucidate the anti-tumor effects and molecular mechanisms of SAHA on the aggressive phenotypes of ovarian carcinoma. Two pairs of cell lines (SKOV3 and SKOV3/DDP; HO8910 and HO8910-PM) were exposed to SAHA treatment, and the effects on acetyl-Histone H3 and H4 expression levels were analyzed and compared against the aggressive behaviors of ovarian carcinoma. Our results showed that SAHA suppressed proliferation in both a concentration- and time-dependent manner in all four cell lines; induced S/G2 arrest in SKOV3 and SKOV3/DDP cells; and conversely, induced G1 arrest in HO8910 and HO8910-PM cells. SAHA treatment induced apoptosis and reduced migration, invasion and lamellipodia formation in the ovarian carcinoma cells; furthermore, SAHA decreased expression of Cyclin B1 and CDC2P34 mRNA, and downregulated CDC2P34, Erk1/2, CyclinB1 and MMP-9 proteins. In contrast, SAHA increased expression of Caspase-3, p21 and p53 mRNA, and upregulated acetyl-Histones H3 and H4, Caspase-8, and p53 proteins. Basal acetylation of histone H3 and H4 was higher in ovarian carcinoma compared to normal ovarian tissues and benign ovarian tumors, and in borderline tumor than in normal ovarian tissues, and was positively correlated with differentiation and expression of the proliferative marker, Ki-67 (P < 0.05). We suggest that SAHA may suppress growth, migration and invasion in ovarian carcinoma cells, including cisplatin-resistant or highly-invasive ovarian cells, by promoting histone acetylation and modulating their phenotype-related molecules. As such, aberrant acetylation of histone H3 and H4 may play an important role in the carcinogenesis and differentiation of ovarian carcinoma.
Department of Gynecology, the First Affiliated Hospital of China Medical University, Shenyang, China.
Shuo
S
Chen
Yang
Y
Zhao
Wen-feng
WF
Gou
Shuang
S
Zhao
Yasuo
Y
Takano
Hua-chuan
HC
Zheng
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D000077337:Vorinostat; D055815:Young Adult
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000077337:Vorinostat