Lysine‐specific demethylase‐1 contributes to malignant behavior by regulation of invasive activity and metabolic shift in esophageal cancer

Abstract

Lysine-specific demethylase-1 (LSD1) removes the methyl groups from mono-and di-methylated lysine 4 of histone H3. Previous studies have linked LSD1 to malignancy in several human tumors, and LSD1 is considered to epigenetically regulate the energy metabolism genes in adipocytes and hepatocellular carcinoma. This study investigates the function of LSD1 in the invasive activity and the metabolism of esophageal cancer cells. We investigated whether LSD1 immunohistochemical expression levels are related to clinical and pathological features, including the maximum standard uptake value in fluorodeoxyglucose positron emission tomography assay. The influence of LSD1 on cell proliferation, invasion and glucose uptake was evaluated in vitro by using specific small interfering RNA for LSD1, and an LSD1 inhibitor. We also evaluated two major energy pathways (glycolytic pathway and mitochondrial respiration) by measuring the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) with an extracellular flux analyzer. High LSD1 immunohistochemical expression was significantly associated with high tumor stage, lymphovascular invasion, poor prognosis, and high maximum standard uptake value in esophageal cancer patients. In the in vitro analysis, LSD1 knockdown significantly suppressed the invasive activity and glucose uptake of cancerous cells, reduced their ECAR and increased their OCR and OCR/ECAR. LSD1 may contribute to malignant behavior by regulating the invasive activity and metabolism, activating the glycolytic pathway and inhibiting the mitochondrial respiration of esophageal cancer cells. The results support LSD1 as a potential therapeutic target.Esophageal cancer is a worldwide concern. Although its geographic distribution varies, it is the eighth most common cancer and the sixth leading cause of cancer mortality. 1 In addition, despite remarkable advances in multimodal therapies combining surgery, chemotherapy, radiotherapy and chemoradiotherapy, the prognosis of esophageal cancer patients remains poor even after complete resection. [2][3][4] Recently, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has become available for assessing the range of tumor progression and predicting prognoses. 5,6 As FDG-PET can also detect the glucose uptake of cancer cells, it may reveal a crucial link between cancer metabolism and malignancy in esophageal cancer.The Warburg effect refers to the shift of glucose metabolism from oxygen-mediated respiration to glycolysis for lactate production. 7 Metabolic switching from oxidative phosphorylation to less energy-efficient glycolysis is characteristic of cancer cells, and the rate of glycolysis is correlated with tumor growth even when oxygen is sufficient.Lysine-specific demethylase-1 (LSD1) is the first reported histone demethylase. LSD1 suppresses gene expression by removing the methyl groups from mono-and di-methylated lysine 4 of histone H3 (H3K4me1/me2). Flavin adenosine Key words: lysine-specific demethylase-1, Warburg effect, esophageal cancer, ...

Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells

“…These data highlight a key role for LSD1 in metabolic reprogramming of HCC cells. Highly similar results were observed in human esophageal cancer (EC), in which LSD1 expression levels were significantly correlated with glucose uptake as detected by fluorodeoxyglucose‐positron emission tomography . In EC cells, LSD1 was essential for the maintenance of glycolytic gene expression.…”

“…Highly similar results were observed in human esophageal cancer (EC), in which LSD1 expression levels were significantly correlated with glucose uptake as detected by fluorodeoxyglucose-positron emission tomography. (58) In EC cells, LSD1 was essential for the maintenance of glycolytic gene expression. Intriguingly, the reduction of glycolytic activity by LSD1 inhibition was accompanied by compromised motility rather than a proliferative defect or cell death, indicating the requirement of metabolic adaptation for cell migration.…”

Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets

“…Additionally, KDM4C overexpression in breast cancer is associated with increased glycolytic metabolism through HIF-1α interaction ( Luo et al, 2012 ) and LSD1 is implicated in gluconeogenesis inhibition through H3K4me2 demethylation, leading to FBP1 and G6P transcription repression ( Pan et al, 2013 ) and favoring HIF-1α-dependent glycolytic metabolism, in hepatocellular carcinoma ( Sakamoto et al, 2015 ). Furthermore, in oesophageal cancer, LSD1 knockdown leads to decreased extracellular acidification, increased oxygen consumption and glucose uptake ( Kosumi et al, 2016 ).…”

Lysine specific demethylase 1 as therapeutic target of cancer

“…1 Inhibition of LSD1 may constitute an efficient way to interfere with tumor growth and invasiveness. 3 In the present study we consider naturally occurring phytochemicals to develop an anti-cancer therapeutic agent. Phytochemicals improve the efficiency of cytotoxic agents, decrease their resistance, lower or alleviate toxic side effects, reduce the risk of tumour lysis syndrome, and detoxify the body as compare to the potential chemotherapeutic drugs.…”