Objective Microbiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.
Design 18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.
Results We have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.
Conclusion F. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.
- colorectal cancer
- glucose metabolism
- intestinal bacteria
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JH, FG and S-YL contributed equally.
Contributors JH, FG and SL performed most of the experiments with assistance from DM, CS, TT, XZ, YX and TS, CW, XZ and JL helped in micro PET-CT scan. TY, YC, JC, MZ and XM contributed in sample collection. YP and QL helped in pathological assays. JH, FG and SL performed most of the statistical analysis, with HC helped in analysis using R software. JH, HC, and JF conceived and supervised the study. JH, FG, and SL wrote most of the manuscript. All authors commented on the manuscript.
Funding This project was supported in part by grants from the State Key R&D Program (2020YFA0509200), National Natural Science Foundation of China (81421001, 81530072, 81830081, 81871901, 81874159, 81790632, 31970718, 81903064); the Program for Professor of Special Appointment (Eastern Scholar No. 201268) at Shanghai Institutions of Higher Learning; the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant (No. 20152512, 20161309); Shu Guang project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (17SG18); Program of Shanghai Young Academic/Technology Research Leader(19XD1422400); Shanghai Municipal Health Commission, Collaborative Innovation Cluster Project (2019CXJQ02).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The Ethics Committees in the Renji Hospital approved the study protocols, and written informed consent was obtained prior to the investigation. All the research was carried out in accordance with the provisions of the Helsinki Declaration of 1975. All mice experiments were conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All of the study procedures were approved by the Institutional Animal Care and Use Committee of Renji Hospital, School of Medicine, Shanghai Jiaotong University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data and source associated with this study are available from the corresponding author on reasonable request.
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