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Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma

Oncogene volume 41, pages 2873–2884 (2022)Cite this article

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Abstract

Sarcomas are difficult to treat and the therapy, even when effective, is associated with long-term and life-threatening side effects. In addition, the treatment regimens for many sarcomas, including Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, are relatively unchanged over the past two decades, indicating a critical lack of progress. Although differentiation-based therapies are used for the treatment of some cancers, the application of this approach to sarcomas has proven challenging. Here, using a CRISPR-mediated gene knockout approach, we show that Inhibitor of DNA Binding 2 (ID2) is a critical regulator of developmental-related genes and tumor growth in vitro and in vivo in Ewing sarcoma tumors. We also identified that homoharringtonine, which is an inhibitor of protein translation and FDA-approved for the treatment of leukemia, decreases the level of the ID2 protein and significantly reduces tumor growth and prolongs mouse survival in an Ewing sarcoma xenograft model. Furthermore, in addition to targeting ID2, homoharringtonine also reduces the protein levels of ID1 and ID3, which are additional members of the ID family of proteins with well-described roles in tumorigenesis, in multiple types of cancer. Overall, these results provide insight into developmental regulation in Ewing sarcoma tumors and identify a novel, therapeutic approach to target the ID family of proteins using an FDA-approved drug.

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Fig. 1: The CRISPR/Cas9-mediated knockout of ID2 in Ewing sarcoma cell lines impairs growth in vitro and in vivo.
Fig. 2: Overexpression of ID2 in NIH3T3 cells increases tumorigenesis in vitro and in vivo.
Fig. 3: ID2 regulates the expression of developmental genes in Ewing sarcoma cells.
Fig. 4: Homoharringtonine (HHT) inhibits protein synthesis and reduces levels of ID proteins in Ewing sarcoma cell lines.
Fig. 5: HHT reduces the levels of the ID1, ID2, and ID3 proteins in sarcoma cell lines.

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Acknowledgements

We would like to acknowledge Henry Keen for assistance with the analysis of the RNA-seq data. DJG is supported by a University of Iowa Dance Marathon Award, a Holden Comprehensive Cancer Center Sarcoma Multidisciplinary Oncology Group Seed Grant, Sammy’s Superheroes, The Matt Morrell and Natalie Sanchez Pediatric Cancer Research Foundation, Aiming for a Cure, and NIH Grant R37-CA217910. This work was also supported by a grant (P30CA086862) from the NCI, administered through the Holden Comprehensive Cancer Center at The University of Iowa. The authors would like to acknowledge use of the University of Iowa Flow Cytometry Facility and the DNA sequencing facility (Genomics Division of the Iowa Institute of Human Genetics) which are supported, in part, by the University of Iowa Carver College of Medicine and the Holden Comprehensive Cancer Center (NCI P30CA086862).

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Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Iowa, Iowa City, IA, 52242, USA

    Stacia L. Koppenhafer, Kelli L. Goss, Emma Croushore, William W. Terry & David J. Gordon

  2. Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Ellen Voigt

  3. Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Minnesota, Minneapolis, MN, 55455, USA

    Jason Ostergaard & Peter M. Gordon

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  1. Stacia L. Koppenhafer
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DJG was responsible for experimental design and conception, data collection and analysis, and interpretation of the results. WWT and PMG contributed to experimental design and data analysis. SLK, KLG, EV, EC, and JO were responsible for collecting and analyzing the data. All authors contributed to the preparation and revision of the manuscript.

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Correspondence to David J. Gordon.

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Koppenhafer, S.L., Goss, K.L., Voigt, E. et al. Inhibitor of DNA binding 2 (ID2) regulates the expression of developmental genes and tumorigenesis in ewing sarcoma. Oncogene 41, 2873–2884 (2022). https://doi.org/10.1038/s41388-022-02310-0

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