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Carbohydrate responsive element binding protein promotes colorectal carcinogenesis via Wnt/β-catenin pathway

Oncogene (2026)Cite this article

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Abstract

Despite significant advances in colorectal cancer (CRC) diagnosis and treatment, drug therapy of CRC patients is still confronted with considerable challenges. Carbohydrate response element-binding protein (ChREBP), a glucose-responsive transcription factor regulating glycolysis and de novo lipogenesis, shows elevated expression in human CRC tissues and correlates with poor disease-free survival and overall survival. However, the in vivo role and mechanism of ChREBP in colorectal carcinogenesis remain unclear. We used ChREBP knockout mice, which were intraperitoneally injected with azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in drinking water. In the AOM/DSS-induced colorectal cancer model, carcinogenesis was reduced in ChREBP null mice. In the initial phases of colorectal carcinogenesis, ChREBP deficiency was associated with diminished epithelial cell proliferation and a lower number of aberrant crypt foci, but it had no impact on DNA damage or the severity of colitis. The key transcription factor β-catenin and Wnt target gene expression were both decreased in the colons of ChREBP null mice and in ChREBP-knockdown Caco-2 colorectal cancer cells. In vitro studies demonstrated that ChREBP overexpression promoted β-catenin accumulation, nuclear translocation, and transcriptional activity by interacting with β-catenin, while ChREBP knockdown produced the opposite effects. These findings establish a novel mechanism whereby ChREBP drives CRC progression through Wnt/β-catenin pathway activation, positioning it as both a potential therapeutic target and prognostic biomarker for CRC.

Working model of ChREBP in promoting Wnt signaling and colorectal carcinogenesis. [Figure created with BioRender.com].

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Fig. 1: ChREBP expression levels correlate with colorectal carcinogenesis and poor survival in CRC patients.
Fig. 2: ChREBP deficiency delays colorectal cancer initiation and progression.
Fig. 3: Reduced aberrant crypt foci and proliferation in ChREBP KO mouse colon compared with control mouse colon.
Fig. 4: Downregulation of Wnt signaling in AOM/DSS-induced ChREBP KO mouse colon.
Fig. 5: Knockdown of ChREBP expression resulted in decreased total and nuclear β-catenin levels in the Caco-2 colorectal cancer cell line.
Fig. 6: ChREBP promotes β-catenin protein level and transcriptional activity by interaction with β-catenin.

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Data availability

RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus database with the following accession codes GSE310284 and are publicly available at the date of publication. Any additional information required to reanalyze the data reported in this paper and the materials generated and used in this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors thank Dr. Lin Li and Dr. Xiaomin Song for providing flag-β-catenin and HA-LEF1. We are grateful to Prof. Yong Zuo for kindly providing the NCM460 cells. This work was supported by the National Natural Science Foundation of China (82173002, 82330080, 82425042, 32371361, 324B200110, 31900562) and the National Key Research and Development Program of China (2019YFA0906100). We appreciate the support from Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases. The authors declare that they have not used AI-generated work in this manuscript.

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  1. These authors contributed equally: Ming Feng, Wenrui He, Guoxiao Ji.

Authors and Affiliations

  1. School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong, China

    Ming Feng & Jian Meng

  2. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wenrui He, Guoxiao Ji, Zhangbing Chen, Yemin Zhu, Ping Zhang, Lukuan Zhang, Yakui Li, Xuemei Tong & Lifang Wu

  3. Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Ministry of Education, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lingfeng Tong

  4. Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China

    Ying Lu

  5. Department of Neurology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China

    Na Tian

  6. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA

    Qi Liu

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Contributions

MF: Writing-original draft, Software, Methodology, Investigation, Data curation, Conceptualization, Funding acquisition. WH: Methodology, Investigation, Data curation. GJ: Methodology, Investigation, Data curation. LT: Methodology, Investigation, Data curation. ZC: Methodology, Investigation, Data curation, Funding acquisition. YZ: Software, Methodology, Data curation. YL: Software, Conceptualization, Data curation. NT: Conceptualization, Methodology, Investigation. QL: Conceptualization, Methodology, Investigation. PZ: Software, Methodology. LZ: Software, Methodology. YL: Software, Methodology, Investigation, Data curation, Conceptualization. XT: Writing-review & editing, Supervision, Resources, Project administration, Funding acquisition, Conceptualization. JM: Software, Methodology, Investigation, Data curation, Conceptualization. LW: Writing-original draft, Writing-review & editing, Software, Methodology, Investigation, Data curation, Funding acquisition, Conceptualization.

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Correspondence to Yakui Li, Xuemei Tong, Jian Meng or Lifang Wu.

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Feng, M., He, W., Ji, G. et al. Carbohydrate responsive element binding protein promotes colorectal carcinogenesis via Wnt/β-catenin pathway. Oncogene (2026). https://doi.org/10.1038/s41388-026-03779-9

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