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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancer types and the second most common cause of death from cancer worldwide [1]
We showed that overexpression of lysine-specific demethylase 1 (LSD1) is a potential prognostic factor in HCC
We found that LSD1 promotes tumorigenesis and malignancy of HCC in vitro; we identified the signaling pathways regulated by LSD1 in HCC cells
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancer types and the second most common cause of death from cancer worldwide [1]. Many studies have revealed that hepatocarcinogenesis has the following multistep process: Activation of oncogenes and inactivation of tumor suppressor genes due to genetic and/or epigenetic events [2,3,4]. The precise molecular mechanisms relevant to HCC development are still uncertain. Since biochemical and genetic mechanisms involved in the development of cancers differ based on cancer type [5], the treatment of each cancer type often requires specified agents; this implies the importance of detailed functional analysis of each cancer type. The three main systems of epigenetic regulation are DNA methylation of gene regulatory regions, covalent modifications of histones, such as methylation and acetylation, and non-coding RNAs
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