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

Keisuke Kosumi, Yoshifumi Baba, Akihisa Sakamoto, Takatsugu Ishimoto, Kazuto Harada, Kenichi Nakamura, Junji Kurashige, Yukiharu Hiyoshi, Masaaki Iwatsuki, Shiro Iwagami, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Eiji Oki, Masayuki Watanabe, Shinjiro Hino, Mitsuyoshi Nakao, Hideo Baba

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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. What's new? How does the enzyme lysine-specific demethylase-1 (LSD)-1 help esophageal cancer cells survive and spread? New results may shed some light on the molecular goings-on that boost the cancer and suggest a way to shut it down. In this article, the authors blocked LSD-1 expression in vitro using small interfering RNAs. The cells producing less LSD-1 had reduced glucose uptake and decreased invasive activity. When they tested the enzyme's effect on energy metabolism pathways, they found that it appears to activate the cancer cells' glycolytic pathway and suppress mitochondrial respiration. Thus, LSD-1 could be useful as a therapeutic target.

Original languageEnglish
Pages (from-to)428-439
Number of pages12
JournalInternational Journal of Cancer
Volume138
Issue number2
DOIs
Publication statusPublished - Jan 15 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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