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Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity

Oncogene volume 38, pages 7504–7520 (2019)Cite this article

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Abstract

Genomic amplification of the oncogene MYCN is a major driver in the development of high-risk neuroblastoma, a pediatric cancer with poor prognosis. Given the challenge in targeting MYCN directly for therapy, we sought to identify MYCN-dependent metabolic vulnerabilities that can be targeted therapeutically. Here, we report that the gene encoding glycine decarboxylase (GLDC), which catalyzes the first and rate-limiting step in glycine breakdown with the production of the one-carbon unit 5,10-methylene-tetrahydrofolate, is a direct transcriptional target of MYCN. As a result, GLDC expression is markedly elevated in MYCN-amplified neuroblastoma tumors and cell lines. This transcriptional upregulation of GLDC expression is of functional significance, as GLDC depletion by RNA interference inhibits the proliferation and tumorigenicity of MYCN-amplified neuroblastoma cell lines by inducing G1 arrest. Metabolomic profiling reveals that GLDC knockdown disrupts purine and central carbon metabolism and reduces citrate production, leading to a decrease in the steady-state levels of cholesterol and fatty acids. Moreover, blocking purine or cholesterol synthesis recapitulates the growth-inhibitory effect of GLDC knockdown. These findings reveal a critical role of GLDC in sustaining the proliferation of neuroblastoma cells with high-level GLDC expression and suggest that MYCN amplification is a biomarker for GLDC-based therapeutic strategies against high-risk neuroblastoma.

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Acknowledgements

We thank John K. Cowell (Augusta University), Susan L. Cohn (University of Chicago), M. Celeste Simon (University of Pennsylvania), and C. Patrick Reynolds (Children’s Oncology Group, Texas Tech University) for providing cell lines, and Rogier Versteeg and the Department of Oncogenomics at the Academic Medical Center (Amsterdam, The Netherlands) for providing the R2 Genomics Analysis and Visualization Platform.

Funding

This work was supported by an NIH grant (R01 CA190429) to HFD.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Ahmet Alptekin, Candace J. Poole, Jan van Riggelen & Han-Fei Ding

  2. Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Ahmet Alptekin, Bingwei Ye, Candace J. Poole, Jan van Riggelen & Han-Fei Ding

  3. Institute of Neural Regeneration and Repair and Department of Neurology, The First Hospital of Yichang, Three Gorges University College of Medicine, 443000, Yichang, China

    Yajie Yu & Yunhong Zha

  4. Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Han-Fei Ding

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Alptekin, A., Ye, B., Yu, Y. et al. Glycine decarboxylase is a transcriptional target of MYCN required for neuroblastoma cell proliferation and tumorigenicity. Oncogene 38, 7504–7520 (2019). https://doi.org/10.1038/s41388-019-0967-3

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