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Lysine-Specific Histone Demethylase 1 Promotes Oncogenesis of the Esophageal Squamous Cell Carcinoma by Upregulating DUSP4

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer (EC) and has a poor prognosis due to its aggressive nature. Accordingly, it is necessary to find novel prognostic biomarkers and therapeutic targets for ESCC. Lysine-specific histone demethylase 1 (LSD1) plays a core role in the regulation of ESCC oncogenesis. However, the detailed mechanism of LSD1-regulated ESCC growth has not been elucidated. This study aims to explore molecular mechanism underlying the LSD1-regulated ESCC’s oncogenesis. After LSD1 silencing, we detected differentially expressed genes (DEGs) in human ESCC cell line, TE-1, by transcriptome sequencing. Subsequently, we investigated expression pattern of the selected molecules in the ESCC tissues and cell lines by qRT-PCR and Western blotting. Furthermore, we explored the roles of selected molecules in ESCC using gene silencing and overexpression assays. Transcriptome sequencing showed that the expression of dual specificity phosphatase 4 (DUSP4) in TE-1 was significantly attenuated after the LSD1 silencing. In addition, the DUSP4 mRNA expression level was significantly higher in the ESCC tissues, especially in those derived from patients with invasion or metastasis. Moreover, the DUSP4 expression was positively associated with the LSD1 expression in the ESCC tissues. DUSP4 overexpression promoted proliferation, invasion, and migration of the ESCC cells, while DUSP4 silencing had an opposite effect. DUSP4 overexpression also enhanced tumorigenicity of the ESCC cells in vivo, while DUSP4 silencing inhibited tumor growth. Importantly, inhibition of cell proliferation, invasion, and migration by the LSD1 inhibitor (ZY0511) was reversed by DUSP4 overexpression. Conclusively, we found that LSD1 promotes ESCC’s oncogenesis by upregulating DUSP4, the potential therapeutic and diagnostic target in ESCC.

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Abbreviations

CCK-8:

Cell Counting Kit-8

DEGs:

differentially expressed genes

DUSP4:

dual specificity phosphatase 4

EC:

esophageal cancer

ESCC:

esophageal squamous cell carcinoma

H3K4me2:

histone H3 di-methylation at lysine 4

LSD1:

lysine-specific histone demethylase 1

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Funding

This work was supported by the Basic Scientific Research Projects of Fujian Provincial Public Welfare Scientific Research Institutes (2016R1029-2, 2019R1011-3) and by the Fujian Health and Family Planning Scientific Research Talent Training Project (2018-ZQN-20).

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    Authors and Affiliations

    1. Department of Immunization, Fujian Academy of Medical Sciences, 350003, Fuzhou, Fujian, China

      Junyong Han, Jinyan Chen, Kun Wang, Jingjun Jin & Shijie Xue

    2. Fujian Institute of Medical Sciences, Fujian Provincial Key Laboratory of Medical Analysis, 350003, Fuzhou, Fujian, China

      Junyong Han, Jinyan Chen, Kun Wang, Jingjun Jin & Shijie Xue

    3. Department of Cardiothoracic Surgery, 900 Hospital of the Joint Logistics Team, 350025, Fuzhou, Fujian, China

      Shixin Ye & Zhiyong Zeng

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    1. Junyong Han
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    Han, J., Ye, S., Chen, J. et al. Lysine-Specific Histone Demethylase 1 Promotes Oncogenesis of the Esophageal Squamous Cell Carcinoma by Upregulating DUSP4. Biochemistry Moscow 86, 1624–1634 (2021). https://doi.org/10.1134/S0006297921120117

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