title: Histone deacetylase 4 increases progressive epithelial ovarian cancer cells via repression of p21 on fibrillar collagen matrices.
abstract: Histone deacetylase (HDAC) 4 is an emerging target in cancer therapeutics, but little is known about the function of HDAC4 in gynecologic malignancies. Therefore we investigated the mechanism of HDAC4 promoting the proliferation of epithelial ovarian cancer cells (OV). In this study, we observed that the proliferation of cells with HDAC4 inhibitor Trichostatin A (TSA) treatment was markedly decreased, Further, we showed that epithelial ovarian cancer tissues with stage III/IV had higher HDAC4 expression, compared to that with stage I/II. We examined first that the HDAC4 expression was increased in response to fibrillar collagen matrices. In addition, we found that HDAC4 was retained in the nucleus by regulation of PP1α, which regulated HDAC4 cellular fraction via phosphorylation of HDAC4. In addition, we found that HDAC4 bound to Sp1 in epithelial ovarian cancer cells. Finally, ovarian cancer cell line OVCAR3 was evaluated via gain/loss-of-function of HDAC4 by either overexpression of HDCA4 or knock-down of HDAC4 with shRNA. We examined both protein and mRNA of p21 by western blotting and qPCR. We performed analysis of colony formation in matrigel and migration by ECIS. Our results suggest that the accumulation of HDAC4 induced by fibrillar collagen matrices in the nucleus via co-localization of PP1α, leads to repression of the mRNA/protein of p21 and in turn promotes the proliferation and migration of epithelial ovarian cancer cells.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Gynecology and Obstetrics, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Gynecology and Obstetrics, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Gynecology and Obstetrics, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Kou
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Gynecology and Obstetrics, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Qiao-Ying
authors.initials: QY
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Gynecology and Obstetrics, Nanjing Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005260:Female; D024022:Fibrillar Collagens / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D024022:Fibrillar Collagens; D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases