Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines

Abstract

BackgroundLysine-specific demethylase 1 (LSD1, also known as KDM1A and AOF2) is a chromatin-modifying activity that catalyzes the removal of methyl groups from lysine residues in histone and non-histone proteins, regulating gene transcription. LSD1 is overexpressed in several cancer types, and chemical inhibition of the LSD1 activity has been proposed as a candidate cancer therapy. Here, we examine the levels of LSD1 mRNA in human ovarian tumors and the cytotoxicity of several chemical LSD1 inhibitors in a panel of ovarian cancer cell lines.MethodsWe measured LSD1 mRNA levels in a cohort of n = 177 normal and heterogeneous tumor specimens by quantitative real time-PCR (qRT-PCR). Tumors were classified by FIGO stage, FIGO grade, and histological subtypes. We tested the robustness of our analyses in an independent cohort of n = 573 serous tumor specimens (source: TCGA, based on microarray). Statistical analyses were based on Kruskal-Wallis/Dunn’s and Mann Whitney tests. Changes in LSD1 mRNA levels were also correlated with transcriptomic alterations at genome-wide scale. Effects on cell viability (MTS/PMS assay) of six LSD1 inhibitors (pargyline, TCP, RN-1, S2101, CAS 927019-63-4, and CBB1007) were also evaluated in a panel of ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and cisplatin-resistant A2780cis).ResultsWe found moderate but consistent LSD1 mRNA overexpression in stage IIIC and high-grade ovarian tumors. LSD1 mRNA overexpression correlated with a transcriptomic signature of up-regulated genes involved in cell cycle and down-regulated genes involved in the immune/inflammatory response, a signature previously observed in aggressive tumors. In fact, some ovarian tumors showing high levels of LSD1 mRNA are associated with poor patient survival. Chemical LSD1 inhibition induced cytotoxicity in ovarian cancer lines, which roughly correlated with their reported LSD1 inhibitory potential (RN-1,S2101 >> pargyline,TCP).ConclusionsOur findings may suggest a role of LSD1 in the biology of some ovarian tumors. It is of special interest to find a correlation of LSD1 mRNA overexpression with a transcriptomic signature relevant to cancer. Our findings, therefore, prompt further investigation of the role of LSD1 in ovarian cancer, as well as the study of its enzymatic inhibition in animal models for potential therapeutic purposes in the context of this disease.

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

“…LSD1 family members are capable of removing the H3K4me2-activating marks and rendering them potential players in the downregulation of tumor suppressors (40,41). The putative role of LSD1 as an oncogene in cancer development is supported by the observation that LSD1 is highly expressed in ovarian cancer (13,14) and other malignant tumors (5-10). LSD1 is reported to play an important role in ovarian cancer cell proliferation via a Sox2-mediated mechanism (31).…”

“…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.…”

Lysine-Specific Demethylase 1 (LSD1) Inhibitor S2101 Induces Autophagy via the AKT/mTOR Pathway in SKOV3 Ovarian Cancer Cells

“…It can also demethylate non-histone lysine residues [8]. LSD1 has been found to be overexpressed in various cancers, including ovarian cancer [9,10], breast cancer [11], colon cancer [12], and gastric cancer [13]. LSD1 is flavin adenine dinucleotides-dependent (FAD) amine oxidase [9].…”

“…LSD1 has been found to be overexpressed in various cancers, including ovarian cancer [9,10], breast cancer [11], colon cancer [12], and gastric cancer [13]. LSD1 is flavin adenine dinucleotides-dependent (FAD) amine oxidase [9]. FDA-approved inhibitors of FAD amine oxidases such as mitochondrial-associated monoamine oxidase (MAO) A and B and polyamine oxidase (PAO) are non-selective inhibitors of LSD1 activity [14].…”

Downregulation of LSD1 suppresses the proliferation, tumorigenicity and invasion of papillary thyroid carcinoma K1 cells

“…Epigenetic changes in LSD1 have been shown to play a key role in carcinogenesis. LSD1 is regarded as a predictive marker for malignant transformation as the overexpression of LSD1 is associated with poor differentiation and poor survival (31,(34)(35)(36). LSD1 promotes the growth, invasion and migration of cancer cells (28), while inhibiters of LSD1 suppress the proliferation, migration and invasion of cancer cells (30,32,37).…”