Deregulation of the histone lysine-specific demethylase 1 is involved in human hepatocellular carcinoma

Sangchul Kim, Amina Bolatkan, Syuzo Kaneko, Noriko Ikawa, Ken Asada, Masaaki Komatsu, Shinya Hayami, Hidenori Ojima, Nobutsugu Abe, Hiroki Yamaue, Ryuji Hamamoto

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2 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. In order to tackle this issue, we conducted functional analysis of the histone lysine-specific demethylase (LSD1) to explore the possibility that this enzyme acts as a therapeutic target in HCC. According to immunohistochemical analysis, 232 of 303 (77%) HCC cases showed positive staining of LSD1 protein, and its expression was correlated with several clinicopathological characteristics, such as female gender, AFP (alpha-fetoprotein) levels, and HCV (hepatitis C virus) infectious. The survival curves for HCC using the Kaplan–Meier method and the log-rank test indicate that positive LSD1 protein expression was significantly associated with decreased rates of overall survival (OS) and disease-free survival (DFS); the multivariate analysis indicates that LSD1 expression was an independent prognostic factor for both OS and DFS in patients with HCC. In addition, knockout of LSD1 using the CRISPR/Cas9 system showed a significantly lower number of colony formation units (CFUs) and growth rate in both SNU-423 and SNU-475 HCC cell lines compared to the corresponding control cells. Moreover, LSD1 knockout decreased cells in S phase of SNU-423 and SNU-475 cells with increased levels of H3K4me1/2 and H3K9me1/2. Finally, we identified the signaling pathways regulated by LSD1 in HCC, including the retinoic acid (RA) pathway. Our findings imply that deregulation of LSD1 can be involved in HCC; further studies may explore the usefulness of LSD1 as a therapeutic target of HCC.

Original languageEnglish
Article number810
JournalBiomolecules
Volume9
Issue number12
DOIs
Publication statusPublished - 2019 Dec

Keywords

  • Hepatocellular carcinoma
  • Histone demethylase
  • LSD1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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    Kim, S., Bolatkan, A., Kaneko, S., Ikawa, N., Asada, K., Komatsu, M., Hayami, S., Ojima, H., Abe, N., Yamaue, H., & Hamamoto, R. (2019). Deregulation of the histone lysine-specific demethylase 1 is involved in human hepatocellular carcinoma. Biomolecules, 9(12), [810]. https://doi.org/10.3390/biom9120810