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NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma

Oncogene volume 40, pages 6736–6747 (2021)Cite this article

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Abstract

Tumor metabolic reprogramming ensures that cancerous cells obtain sufficient building blocks, energy, and antioxidants to sustain rapid growth and for coping with oxidative stress. Neurogenic differentiation factor 1 (NeuroD1) is upregulated in various types of tumors; however, its involvement in tumor cell metabolic reprogramming remains unclear. In this study, we report that NeuroD1 is positively correlated with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP), in colorectal cancer cells. In addition, the regulation of G6PD by NeuroD1 alters tumor cell metabolism by stimulating the PPP, leading to enhanced production of nucleotides and NADPH. These, in turn, promote DNA and lipid biosynthesis in tumor cells, while decreasing intracellular levels of reactive oxygen species. Mechanistically, we showed that NeuroD1 binds directly to the G6PD promoter to activate G6PD transcription. Consequently, tumor cell proliferation and colony formation are enhanced, leading to increased tumorigenic potential in vitro and in vivo. These findings reveal a novel function of NeuroD1 as a regulator of G6PD, whereby its oncogenic activity is linked to tumor cell metabolic reprogramming and regulation of the PPP. Furthermore, NeuroD1 represents a potential target for metabolism-based anti-tumor therapeutic strategies.

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Fig. 1: NeuroD1 alters tumor cells glucose metabolism.
Fig. 2: NeuroD1 promotes tumor cells pentose phosphate pathway (PPP).
Fig. 3: G6PD is crucial for NeuroD1-induced tumor cells PPP.
Fig. 4: NeuroD1 enhances tumor cells PPP in a p53-independent manner.
Fig. 5: NeuroD1 enhances G6PD expression by directly regulating its transcription.
Fig. 6: NeuroD1/G6PD axis promotes colorectal cancer cell tumorigenesis potential.
Fig. 7: Schematic diagram showing the regulation mechanism of NeuroD1 on CRC tumorigenesis via G6PD-induced PPP.

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Acknowledgements

We thank Dr. Bert Vogelstein (School of Medicine, Johns Hopkins University) for kindly providing wild-type and p53-null HCT116p53null cell lines. This work was supported by grants from the National Natural Science Foundation of China (11832008, 31871367, and 81872273); and the Natural Science Foundation of Chongqing (cstc2018jcyjAX0411 and cstc2018jcyjAX0374).

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  1. These authors contributed equally: Zhuolin Li, Yuxin He, Yanjun Li.

Authors and Affiliations

  1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Zhuolin Li, Yuxin He, Yanjun Li, Juan Li, Guanbing Song, Shourong Wu & Vivi Kasim

  2. The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, 400044, China

    Zhuolin Li, Yuxin He, Yanjun Li, Juan Li, Shourong Wu & Vivi Kasim

  3. Department of Gastrointestinal Surgery, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China

    Hezhao Zhao

  4. Molecular Composite Medicine Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan

    Makoto Miyagishi

  5. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing University, Chongqing, 400030, China

    Shourong Wu & Vivi Kasim

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Contributions

V.K. and S.W. conceived the project, analyzed and interpreted the experimental results; V.K. designed the most experiments of the project and wrote the manuscript. Z.L., Y.H., and Y.L. performed most of the experiments. J.L. performed part of plasmid constructions and cell counting assay. G.S. analyzed part of the data and provided part of the material. H.Z. collected human clinical samples and performed clinical samples analysis. M.M. designed shRNA target sites and analyzed part of the data.

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Correspondence to Shourong Wu or Vivi Kasim.

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Li, Z., He, Y., Li, Y. et al. NeuroD1 promotes tumor cell proliferation and tumorigenesis by directly activating the pentose phosphate pathway in colorectal carcinoma. Oncogene 40, 6736–6747 (2021). https://doi.org/10.1038/s41388-021-02063-2

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