Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization

• Published in: Cell death & disease 2019-01, Vol.10 (2), p.40, Article 40
• Main Authors: Xiang, Lisha, Mou, Jun, Shao, Bin, Wei, Yuquan, Liang, Houjie, Takano, Naoharu, Semenza, Gregg L., Xie, Ganfeng
• Format: Article
• Language: English
• Subjects: 13; 13/105; 13/51; 38; 38/43; 38/61; 38/77; 64; 64/60; 692/699/67/322; 692/699/67/327; 82; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinogenesis; Cell Biology; Cell Culture; Cell Hypoxia - physiology; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; Colonization; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Gene expression; Genomes; Glutaminase; Glutaminase - genetics; Glutaminase - metabolism; Glutamine; Heterografts; HT29 Cells; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-inducible factors; Immunology; Life Sciences; Lymph nodes; Male; Metastases; Metastasis; Mice; Mice, SCID; Mitochondria; Mortality; Neoplasm Metastasis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Survival Analysis; Transcription activation; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1291-5

Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.