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Open AccessArticle

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

1
Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Department of Gastroenterological and General Surgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
3
Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
4
Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8510, Japan
5
Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
*
Authors to whom correspondence should be addressed.
Biomolecules 2019, 9(12), 810; https://doi.org/10.3390/biom9120810
Received: 31 October 2019 / Revised: 23 November 2019 / Accepted: 26 November 2019 / Published: 1 December 2019
(This article belongs to the Special Issue Epigenetics in Cancer)
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.
Keywords: hepatocellular carcinoma; LSD1; histone demethylase hepatocellular carcinoma; LSD1; histone demethylase
MDPI and ACS Style

Kim, S.; Bolatkan, A.; Kaneko, S.; Ikawa, N.; Asada, K.; Komatsu, M.; Hayami, S.; Ojima, H.; Abe, N.; Yamaue, H.; Hamamoto, R. Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma. Biomolecules 2019, 9, 810.

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