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Colorectal Cancer Cell Differentiation Is Dependent on the Repression of Aerobic Glycolysis by NDRG2-TXNIP Axis

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Abstract

Background

Poorly differentiated colorectal cancers are more aggressive. Metabolism reprogramming is a significant hallmark in cancer, and aerobic glycolysis is common. However, how cancer cells reprogramming glucose metabolism contributes to cell differentiation was largely unknown. Previous studies have reported that tumor suppressor NDRG2 could promote colorectal cancers differentiation.

Aims

This study aims to demonstrate that NDRG2 promotes the differentiation of colorectal cancers, potentially through the inhibition of aerobic glycolysis via TXNIP induction.

Methods

Western blotting, qRT-PCR and immunohistochemical staining were used to detect the expression of related molecules. MTT assay was used to reflect cell viability and proliferation. Immunofluorescent assay was performed to identify the expression and distribution of molecules. Luciferase analysis and CHIP assays were used to investigate the mechanism. Bioinformatic analysis was performed to predict the relevance.

Results

In colorectal cancers, NDRG2 could inhibit cell proliferation, reduce glucose uptake and decrease expression of key glycolysis enzymes. Upregulated NDRG2 is associated with differentiated cancer. However, deletion of TXNIP, a classic glucose metabolism inhibitor, could obviously alter the function of NDRG2 in differentiation, glucose uptake, expression of key glycolysis enzymes and proliferation. Mechanistically, high glucose flux promotes the activity of TXNIP promoter. And NDRG2 promotes the occupancy of transcription factor Mondo A on TXNIP promoter, predominantly through the suppression of c-myc, which could complete with Mondo A binding to TXNIP promoter. In clinical samples, high expression of TXNIP indicates good prognosis and outcome.

Conclusions

NDRG2-dependent induction of TXNIP is critical for the aerobic glycolysis during colorectal cancers differentiation.

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Acknowledgments

This work was financially sponsored by grants from the National Natural Science Foundation of China (No. 82073053, No.81702845, No.81502370), the Key Research and Development Plan in Shaanxi Province of China (2020SF-081), the Natural Science Basic Research Plan in Shaanxi Province of China (2019JQ-879), the State Key Laboratory of Cancer Biology Project (CBSKL2019ZZ12; CBSKL2019KF03).

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Author notes

  1. Junbi Hu, Lin Feng these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Junbi Hu, Mudan Ren, Yan Zhao, Guifang Lu, Xinlan Lu, Yarui Li, Xin Wang & Shuixiang He

  2. College of Basic Medicine, Jiamusi University, Jiamusi, 154002, China

    Lin Feng

  3. The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Shaanxi, Xi’an, 710032, China

    Xin Bu, Shuai Wang & Liangliang Shen

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  1. Junbi Hu
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Hu, J., Feng, L., Ren, M. et al. Colorectal Cancer Cell Differentiation Is Dependent on the Repression of Aerobic Glycolysis by NDRG2-TXNIP Axis. Dig Dis Sci 67, 3763–3772 (2022). https://doi.org/10.1007/s10620-021-07188-8

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