Abstract
BackgroundRecent studies suggested the globin family member cytoglobin (CYGB) as a potential tumor suppressor; however, the mechanism by which CYGB suppresses cancer is elusive. We investigated the role and mechanism of CYGB in suppressing breast cancer.MethodsCYGB expression was examined by reverse transcription PCR, quantitative reverse transcription PCR and open database analysis. Promoter methylation was examined by methylation-specific PCR. Metabolomics and proteomics were analyzed by gas chromatography-mass spectrometry and isobaric tags for relative and absolute quantitation, respectively. The effects and mechanisms of ectopic CYGB expression in breast cancer cells were assessed with molecular biological and cellular approaches in vitro and with a xenograft tumor model in nude mice.ResultsCYGB expression was downregulated in breast cancer tissues and cell lines, which was associated with promoter methylation. Ectopic CYGB expression suppressed proliferation, migration, invasion and induced apoptosis in breast cancer cell lines MCF7 (p53WT) and MB231 (p53mt) in vitro, and inhibited xenograft tumor growth in vivo. By proteomics and metabolomics analysis, glucose metabolism was found to be one of the main pathways suppressed by CYGB. The CYGB-expressing cells had lower ATP and compromised glycolysis. Additionally, CYGB suppressed key glucose metabolism factors including GLUT1 and HXK2 in p53-dependent and -independent manners. Restoration of GLUT1 or HXK2 expression attenuated CYGB-mediated proliferation suppression and apoptosis induction.ConclusionsCYGB is a potential tumor suppressor in breast cancer that is epigenetically suppressed. The results for the first time suggest that CYGB suppresses breast cancer through inhibiting glucose metabolism, which could be exploited for breast cancer prevention and therapy.
Highlights
Recent studies suggested the globin family member cytoglobin (CYGB) as a potential tumor suppressor; the mechanism by which CYGB suppresses cancer is elusive
Epigenetic CYGB downregulation in breast cancer is correlated with unfavorable patient survival To investigate the role of CYGB in breast cancer, we first examined its expression in paired tumor and tumor adjacent tissues from 17 patients
The results were validated with The Cancer Genome Atlas (TCGA) dataset with 489 cases, which showed a significant decrease of CYGB expression in breast cancer that includes both invasive ductal breast carcinomas (IDBC) and invasive lobular breast carcinomas (ILBC) (Additional file 2: Figure S1A)
Summary
Recent studies suggested the globin family member cytoglobin (CYGB) as a potential tumor suppressor; the mechanism by which CYGB suppresses cancer is elusive. We investigated the role and mechanism of CYGB in suppressing breast cancer. The heterogeneous characteristics of breast cancer have severely impeded the efforts to combat this deadly disease. Despite our Globins belong to a family of proteins characterized by the ability to bind and transport oxygen. Some well-known members of this family such as hemoglobin and myoglobin play crucial roles in maintaining tissue oxygenation. Novel members of the family such as cytoglobin (CYGB) have been identified to play unique roles under certain conditions. CYGB expression is elevated in many cell types during tissue
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