Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer

Hao Yang; Shifeng Yang; Jixing He; Wenqiang Li; Ange Zhang; Nana Li; Guangkai Zhou; Boshi Sun

doi:10.1186/s12935-023-03162-8

Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer

Cancer Cell Int. 2023 Dec 1;23(1):303. doi: 10.1186/s12935-023-03162-8.

Authors

Hao Yang^#^{1

2}, Shifeng Yang^#¹, Jixing He^#¹, Wenqiang Li³, Ange Zhang¹, Nana Li¹, Guangkai Zhou⁴, Boshi Sun⁵

Affiliations

¹ Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
² Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
³ Department of General Surgery, Jinshan Hospital of Fudan University, Shanghai, China.
⁴ Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, China. zgk.8800@163.com.
⁵ Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. sunboshi1988@126.com.

^# Contributed equally.

Abstract

Objectives: Glucose transporter 3 (GLUT3) plays a major role in glycolysis and glucose metabolism in cancer cells. We aimed to investigate the correlation between GLUT3 and histone lactylation modification in the occurrence and progression of gastric cancer.

Materials and methods: We initially used single-cell sequencing data to determine the expression levels of GLUT3 and lactate dehydrogenase A (LDHA) in primary tumor, tumor-adjacent normal, and metastasis tumor tissues. Immunohistochemistry analysis was conducted to measure GLUT3, LDHA, and L-lactyl levels in gastric normal and cancer tissues. Transwell and scratch assays were performed to evaluate the metastatic and invasive capacity of gastric cancer cell lines. Western blotting was used to measure L-lactyl and histone lactylation levels in gastric cancer cell lines.

Results: Single-cell sequencing data showed that GLUT3 expression was significantly increased in primary tumor and metastasis tumor tissues. In addition, GLUT3 expression was positively correlated with that of LDHA expression and lactylation-related pathways. Western blotting and immunohistochemistry analyses revealed that GLUT3 was highly expressed in gastric cancer tissues and cell lines. GLUT3 knockdown in gastric cancer cell lines inhibited their metastatic and invasive capacity to various degrees. Additionally, the levels of LDHA, L-lactyl, H3K9, H3K18, and H3K56 significantly decreased after GLUT3 knockdown, indicating that GLUT3 affects lactylation in gastric cancer cells. Moreover, LDHA overexpression in a GLUT3 knockdown cell line reversed the levels of lactylation and EMT-related markers, and the EMT functional phenotype induced by GLUT3 knockdown. The in vivo results were consistent with the in vitro results.

Conclusions: This study suggests the important role of histone lactylation in the occurrence and progression of gastric cancer, and GLUT3 may be a new diagnostic marker and therapeutic target for gastric cancer.

Keywords: Epithelial-mesenchymal transition; Gastric cancer; Glucose transporter 3; Lactate dehydrogenase A; Lactylation.

Abstract

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