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

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.

Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection

“…The diverse biological roles of epigenetics and RNA modifications or epitranscriptomics have been elucidated, and epigenetic aberrations have been associated with various types of diseases, including cancer [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. Focusing on RNA modifications, studies of m 6 A are a new boundary of disease, as we reviewed in this paper.…”

Lysine-specific histone demethylase 1A (LSD1) in cervical cancer

“…LSD1 is a histone lysine demethylase and functions as an important transcriptional corepressor by demethylating H3K4me2/me1 and H3K9me2/me1 (Shi et al 2004 ). Prior studies have already described that dysregulation of LSD1 can influence cancer development: Overexpression of LSD1 correlates with poor prognosis in various cancer types like bladder cancer (Hayami et al 2011 ), colon cancer (Jie et al 2013 ) or hepatocellular carcinoma (Kim et al 2019 ). Our result are contrary to a previous study by Liu et al ( 2017 ) who could not find a statistically significant difference in overall nor in tumor free survival for cervical cancer patients with a high or low expression of LSD1 (Liu et al 2017 ).…”

Epigenetic Mechanisms Involved in HCV-Induced Hepatocellular Carcinoma (HCC)

“…With the Kaplan-Meier method, LSD1 protein is shown to decrease rates of overall survival and disease-free survival and regarded as an independent prognostic factor in HCC patients. LSD1 knockout cells display a higher level of H3K4me1/2 and H3K9me1/2 than normal cells (76). Histone lysine or arginine methylase, including G9a, EZH2, SUV39H1, and SUV39H2, tightly associate with the progression of HCC prognosis.…”