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

Research output: Contribution to journalArticle

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

Fingerprint

Histone Demethylases
Deregulation
Liver
Histones
Lysine
Hepatocellular Carcinoma
Clustered Regularly Interspaced Short Palindromic Repeats
Functional analysis
alpha-Fetoproteins
Tretinoin
Viruses
Proteins
Cells
Enzymes
Liver Neoplasms
Disease-Free Survival
Molecular Targeted Therapy
Survival
Standard of Care
S Phase

Keywords

  • Hepatocellular carcinoma
  • Histone demethylase
  • LSD1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Kim, S., Bolatkan, A., Kaneko, S., Ikawa, N., Asada, K., Komatsu, M., ... 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

Deregulation of the histone lysine-specific demethylase 1 is involved in human hepatocellular carcinoma. / Kim, Sangchul; Bolatkan, Amina; Kaneko, Syuzo; Ikawa, Noriko; Asada, Ken; Komatsu, Masaaki; Hayami, Shinya; Ojima, Hidenori; Abe, Nobutsugu; Yamaue, Hiroki; Hamamoto, Ryuji.

In: Biomolecules, Vol. 9, No. 12, 810, 12.2019.

Research output: Contribution to journalArticle

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, vol. 9, no. 12, 810. https://doi.org/10.3390/biom9120810
Kim, Sangchul ; Bolatkan, Amina ; Kaneko, Syuzo ; Ikawa, Noriko ; Asada, Ken ; Komatsu, Masaaki ; Hayami, Shinya ; Ojima, Hidenori ; Abe, Nobutsugu ; Yamaue, Hiroki ; Hamamoto, Ryuji. / Deregulation of the histone lysine-specific demethylase 1 is involved in human hepatocellular carcinoma. In: Biomolecules. 2019 ; Vol. 9, No. 12.
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AU - Komatsu, Masaaki

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AB - 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.

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