Abstract. Lysine-specific demethylase 1 (LSD1) has been implicated in the process of tumor progression at various steps, but its role in epithelial-messenchymal transition (EMT) and the migration of ovarian cancer cells remains obscure.In this study, we demonstrated the effect of LSD1 on ovarian cancer cell migration and the regulatory role of LSD1 in the expression of EMT markers. Inhibition of LSD1 expression impaired the migration and invasion of HO8910 ovarian cancer cells. In contrast, overexpression of LSD1 enhanced the cell migration and invasion of HO8910 cells. Mechanistic analyses showed that LSD1 promoted cell migration through induction of N-cadherin, vimentin, MMP-2 and inhibition of E-cadherin. Furthermore, LSD1 interacted with the promoter of E-cadherin and demethylated histone H3 lysine 4 (H3K4) at this region, downregulated E-cadherin expression, and consequently enhanced ovarian cancer cell migration. These data indicate that LSD1 acts as an epigenetic regulator of EMT and contributes to the metastasis of ovarian cancer. IntroductionOvarian cancer is the second most common cancer among female gynecologic cancers and has become the leading cause of cancer-related death among females (1). Due to the difficulty in early detection, 75% of ovarian cancer patients are diagnosed at advanced stages (stage III or IV) (2). In stage III or IV, the tumor involves one or both ovaries with peritoneal metastasis outside the pelvis or distant metastasis to liver parenchyma or other visceral organs (2,3). Early invasion and metastasis have been well accepted as the leading features and main causes of death in ovarian cancer. However, mechanistic understanding of the metastatic potential of ovarian cancer remains unclear, and novel targets are yet to be identified for treating metastatic ovarian cancer.Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2) is the first histone demethylase discovered, which specifically demethylates mono-and dimethylated histone H3 lysine 4 (H3K4) and histone H3 lysine 9 (H3K9) (4). LSD1 is frequently overexpressed in lung cancer (5,6), breast cancer (7), prostate cancer (8,9), and liver cancer (10). Importantly, overexpression of LSD1 promotes the growth and invasion of various types of cancer cells, and contributes to human carcinogenesis by regulating the expression of genes involved in various chromatin-modifying pathways (6). Conversely, inhibition of LSD1 was found to suppress cell invasion and migration in various types of cancers (5,11,12). Although LSD1 is recently described to be highly expressed in ovarian cancer (13,14), the biological function of LSD1 in this cancer remains largely unknown.Epithelial-messenchymal transition (EMT) is a process whereby epithelial cells are programmed into mesenchymal cells (15). EMT is now considered as the initial and essential step in tumor metastasis. During EMT, epithelial cells acquire cell motility by reducing cell-cell junctions, and loss of cell polarity (16,17). E-cadherin, an epithelial marker, has a crucial role in regulating cell-...

Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by modulating histone methylation and has been associated with numerous high-risk cancers. Previously, our group and others identified LSD1 as an upregulated gene in ovarian cancer, and reported that the upregulation of LSD1 was associated with poor prognosis of patients with ovarian cancer. However, the role of LSD1 in ovarian cancer requires further investigation. The present study revealed that the overexpression of LSD1 significantly promoted the proliferation of SKOV3 ovarian cancer cells, while knockdown of LSD1 markedly inhibited cell proliferation and potentiated cisplatin-induced cell apoptosis, supporting LSD1 as an oncogenic protein in ovarian cancer. Mechanistic studies have indicated that LSD1 modulates the expression of cyclin dependent kinase inhibitor 1, Survivin, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X genes, which are known regulators of cell proliferation. Furthermore, LSD1 knockdown plus cisplatin synergistically impaired cell migration via the induction of the epithelial marker E-cadherin and inhibition of the mesenchymal markers, snail family transcriptional repressor 1 and Vimentin. These data of the present study indicated LSD1 as a potential regulator of ovarian cancer cell progression and suggested an unfavorable role of LSD1 in cisplatin-based regimens.

Ovarian tumor is one of the most lethal gynecologic cancers, but differentiation therapy for this cancer is poorly characterized. Here, we show that thrichostatin A (TSA), the well known inhibitor of histone deacetylases (HDACs), can induce cell differentiation in HO8910 ovarian cancer cells. TSA-induced cell differentiation is characterized by typical morphological change, increased expression of the differentiation marker FOXA2, decreased expression of the pluripotency markers SOX2 and OCT4, suppressing cell proliferation, and cell cycle arrest in the G1 phase. TSA also induces an elevated expression of cell cycle inhibitory protein p21Cip1 along with a decrease in cell cycle regulatory protein cyclin D1. Significantly, blockage of epidermal growth factor receptor (EGFR) signaling pathway with specific inhibitors of this signaling cascade promotes the TSA-induced differentiation of HO8910 cells. These results imply that the EGFR cascade inhibitors in combination with TSA may represent a promising differentiation therapy strategy for ovarian cancer.