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Asparagine bioavailability regulates the translation of MYC oncogene

Abstract

Amino acid restriction has recently emerged as a compelling strategy to inhibit tumor growth. Recent work suggests that amino acids can regulate cellular signaling in addition to their role as biosynthetic substrates. Using lymphoid cancer cells as a model, we found that asparagine depletion acutely reduces the expression of c-MYC protein without changing its mRNA expression. Furthermore, asparagine depletion inhibits the translation of MYC mRNA without altering the rate of MYC protein degradation. Of interest, the inhibitory effect on MYC mRNA translation during asparagine depletion is not due to the activation of the general controlled nonderepressible 2 (GCN2) pathway and is not a consequence of the inhibition of global protein synthesis. In addition, both the 5’ and 3’ untranslated regions (UTRs) of MYC mRNA are not required for this inhibitory effect. Finally, using a MYC-driven mouse B cell lymphoma model, we found that shRNA inhibition of asparagine synthetase (ASNS) or pharmacological inhibition of asparagine production can significantly reduce the MYC protein expression and tumor growth when environmental asparagine becomes limiting. Since MYC is a critical oncogene, our results uncover a molecular connection between MYC mRNA translation and asparagine bioavailability and shed light on a potential to target MYC oncogene post-transcriptionally through asparagine restriction.

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Fig. 1: Asparagine starvation suppresses MYC protein expression in ALL cells expressing low-levels of ASNS.
Fig. 2: Asparagine regulates MYC protein expression post-transcriptionally.
Fig. 3: Asparagine regulates the translation of MYC mRNA.
Fig. 4: RNAi inhibition of ASNS suppresses tumor growth and MYC expression following L-asparaginase treatment in a MYC-driven B cell lymphoma model.
Fig. 5: Pharmacological inhibition of aspartate production sensitizes ASNS-high expressing lymphoid cancers to L-asparaginase treatment.

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Acknowledgements

We thank the IUSCC Flow Cytometry Core for the cell sorting, the In Vivo Therapeutic Core for the intravenous lymphoma transplantation, and the Histology Service Core for tissue embedding and sectioning.

Funding

This work was supported by NIH/NCI CA244625, the American Society of Hematologyand the Riley Children Foundation. RCW is supported by NIH/NIGMS GM136331 and isa member of the advisory board of HiberCell, Inc.

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SS and JZ wrote the manuscript. SS and JJ designed and performed experiments, and analyzed the results. GG, JM, MZ, LZ, and JZ performed experiments. KAS, YL, CC, UD, RK, and SB provided critical experimental reagents. CZ analyzed the data. JF, RCW, and JZ designed experiments. JZ provided the conceptual idea and overall supervision of the project.

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Correspondence to Ji Zhang.

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Srivastava, S., Jiang, J., Misra, J. et al. Asparagine bioavailability regulates the translation of MYC oncogene. Oncogene 41, 4855–4865 (2022). https://doi.org/10.1038/s41388-022-02474-9

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