LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion

Abstract

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-...

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

“…Previous studies have shown that inhibition or silencing of LSD1 leads to reduced tumor cell proliferation and migration capacities in vitro, as well as in vivo (28)(29)(30). Here, we could confirm these results using the LSD1 inhibitor HCI-2509 or with siRNA, that also led to reduced cell proliferation and migration capacities in the lung adenocarcinoma cell line PC9 (Supplementary File S1; Supplementary Fig.…”

LSD1 negatively regulates autophagy through the mTOR signaling pathway in ovarian cancer cells

“…Tet-On-shLSD1 plasmid and lentiviral particles were generated as previously described (9). Lipofectamine 2000 reagent (Invitrogen) was used as the transfection reagent and the transfection was performed according to the manufacturer's protocol.…”

“…LSD1 is highly expressed in a variety of carcinomas, including breast (5), lung (6), hepatocarcinoma (7) and ovarian cancer (8). Our previous studies have demonstrated that the overexpression of LSD1 was associated with an aggressive phenotype and poor prognosis of ovarian cancer (9). However, the molecular mechanism underlying the association of the overexpression of LSD1 with the progression of ovarian cancer remains largely unknown.…”

Inactivation of EGFR/AKT signaling enhances TSA-induced ovarian cancer cell differentiation

“…Total cellular proteins were isolated directly from cultures in 100-mm Petri dishes after being washed with ice-cold PbS and the addition of 200 µl Cell and Tissue Protein Extraction reagent (Kangchen biotech, Shanghai, China), containing protease inhibitor and phosphatase inhibitor cocktails (Roche). Antibodies against OCT4 (1:5,000), SOX2 (1:5,000), FOXA2 (1:1,000), cyclin D1 (1:10,000), p21 Cip1 (1:3,000), EGFR (1:1,000), p-EGFR (1:600), AKT (1:1,000), p-AKT (1:800), α-tubulin (1:1,000), and histone H3 (1:2,000) were used for western blot analysis, which was performed as described previously (16).…”