Insulin gene enhancer protein 1 mediates glycolysis and tumorigenesis of gastric cancer through regulating glucose transporter 4

Background Insulin gene enhancer protein 1, (ISL1), a LIM‐homeodomain transcription factor, is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes. However, the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer (GC) is unclear...

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Published in:	Cancer communications (London, England) England), 2021-03, Vol.41 (3), p.258-272
Main Authors:	Guo, Ting, Bai, Yan‐Hua, Cheng, Xiao‐Jing, Han, Hai‐Bo, Du, Hong, Hu, Ying, Jia, Shu‐Qin, Xing, Xiao‐Fang, Ji, Jia‐Fu
Format:	Article
Language:	eng
Subjects:	Acidification Carcinogenesis Cell Line, Tumor Cyclin-dependent kinases Dehydrogenases Experiments Flow cytometry gastric cancer Genes Glucose Glucose Transport Proteins, Facilitative glucose transporter 4 glycolysis Glycolysis - genetics Growth factors Homeostasis Humans Insulin insulin gene enhancer protein 1 Insulins Kinases Medical prognosis Metabolism Metastasis Original Phosphorylation Plasmids Proteins Stomach cancer Stomach Neoplasms - genetics Tumorigenesis
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Summary:	Background Insulin gene enhancer protein 1, (ISL1), a LIM‐homeodomain transcription factor, is involved in multiple tumors and is associated with insulin secretion and metabolic phenotypes. However, the role of ISL1 in stimulating glycolysis to promote tumorigenesis in gastric cancer (GC) is unclear. In this study, we aimed to characterize the expression pattern of ISL1 in GC patients and explore its molecular biological mechanism in glycolysis and tumorigenesis. Methods We analyzed the expression and clinical significance of ISL1 in GC using immunohistochemistry and real‐time polymerase chain reaction (PCR). Flow cytometry and IncuCyte assays were used to measure cell proliferation after ISL1 knockdown. RNA‐sequencing was performed to identify differentially expressed genes, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA) to reveal key signaling pathways likely regulated by ISL1 in GC. Alteration of the glycolytic ability of GC cells with ISL1 knockdown was validated by measuring the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) and by detecting glucose consumption and lactate production. The expression of glucose transporter 4 (GLUT4) and ISL1 was assessed by Western blotting, immunohistochemistry, and immunofluorescent microscopy. The luciferase reporter activity and chromatin immunoprecipitation assays were performed to determine the transcriptional regulation of ISL1 on GLUT4. Results High levels of ISL1 and GLUT4 expression was associated with short survival of GC patients. ISL1 knockdown inhibited cell proliferation both in vitro and in vivo. KEGG analysis and GSEA for RNA‐sequencing data indicated impairment of the glycolysis pathway in GC cells with ISL1 knockdown, which was validated by reduced glucose uptake and lactate production, decreased ECAR, and increased OCR. Mechanistic investigation indicated that ISL1 transcriptionally regulated GLUT4 through binding to its promoter. Conclusion ISL1 facilitates glycolysis and tumorigenesis in GC via the transcriptional regulation of GLUT4. This study revealed that ISL1 modulates tumorigenesis and glycolysis in GC, wherein GLUT4 plays pivotal roles. Moreover, ISL1 and GLUT4 are predictive markers of a poor prognosis in patients with GC, which might hold therapeutic potential for this lethal malignancy.
ISSN:	2523-3548 2523-3548