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The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors

Oncogene volume 40, pages 564–577 (2021)Cite this article

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Abstract

Ribonucleotide reductase (RNR), which is a heterodimeric tetramer composed of RRM1 and RRM2 subunits, is the rate-limiting enzyme in the synthesis of deoxyribonucleoside triphosphates (dNTPs) and essential for both DNA replication and the repair of DNA damage. The activity of RNR is coordinated with the cell cycle and regulated by fluctuations in the level of the RRM2 subunit. Multiple cancer types, including Ewing sarcoma tumors, are sensitive to inhibitors of RNR or a reduction in the levels of either the RRM1 or RRM2 subunits of RNR. Here, we show that the expression of the RRM2 protein is dependent on active protein synthesis and that 4E-BP1, a repressor of cap-dependent protein translation, specifically regulates the level of the RRM2 protein. Furthermore, inhibition of mTORC1/2, but not mTORC1, activates 4E-BP1, inhibits protein synthesis, and reduces the level of the RRM2 protein in multiple sarcoma cell lines. This effect of mTORC1/2 inhibitors on protein synthesis and RRM2 levels was rescued in cell lines with the CRISPR/Cas9-mediated knockout of 4E-BP1. In addition, the inducible expression of a mutant 4E-BP1 protein that cannot be phosphorylated by mTOR blocked protein synthesis and inhibited the growth of Ewing sarcoma cells in vitro and in vivo in a xenograft. Overall, these results provide insight into the multifaceted regulation of RRM2 protein levels and identify a regulatory link between protein translation and DNA replication.

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Fig. 1: ATR-CHK1 inhibitors and homoharringtonine selectively target Ewing sarcoma cells with a partial reduction in the level of the RRM2 protein.
Fig. 2: HHT inhibits protein synthesis and reduces the level of the RRM2 protein in Ewing sarcoma cell lines.
Fig. 3: Inhibition of mTORC1/2 activates 4E-BP1, blocks protein synthesis, and reduces the level of the RRM2 protein.
Fig. 4: The CRISPR/Cas9-mediated knockout of 4E-BP1 in Ewing sarcoma cell lines rescues the effects of mTORC1/2 inhibitors on protein synthesis.
Fig. 5: The inducible expression of constitutively active 4E-BP1 reduces the level of the RRM2 protein and protein synthesis in sarcoma cells.
Fig. 6: Integrated model for the regulation of RRM2 protein levels by the mTORC1/2, ATR-CHK1, and WEE1 pathways.

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Acknowledgements

DJG is supported by a University of Iowa Dance Marathon Award, a Holden Comprehensive Cancer Center Sarcoma Multidisciplinary Oncology Group Seed Grant, a University of Iowa Oberley Seed Grant, St. Baldrick’s Research Foundation, Aiming for a Cure Foundation, The Matt Morrell and Natalie Sanchez Pediatric Cancer Research Foundation, and NIH Grant R37-CA217910. We would also like to acknowledge the use of the University of Iowa Flow Cytometry and High Throughput Screening Core Facilities (NIH/NCI P30CA086862), as well as the RPPA Core Facility at MD Anderson Cancer Center (NCI # CA16672).

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

    Kelli L. Goss, Stacia L. Koppenhafer, Torin Waters, William W. Terry & David J. Gordon

  2. Department of Biochemistry, University of Iowa, Iowa City, IA, 52242, USA

    Kuo-Kuang Wen & Meng Wu

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

    Jason Ostergaard & Peter M. Gordon

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Goss, K.L., Koppenhafer, S.L., Waters, T. et al. The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors. Oncogene 40, 564–577 (2021). https://doi.org/10.1038/s41388-020-01552-0

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