Asparagine bioavailability regulates the translation of MYC oncogene

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Amino acid restriction is a novel strategy for inhibiting tumor growth.
• Amino acids regulate cellular signaling pathways beyond their role in biosynthesis.
• The oncogene MYC is crucial in lymphoid cancers.

Purpose of the Study:

• To investigate the effect of asparagine depletion on MYC protein expression and translation in lymphoid cancer cells.
• To elucidate the molecular mechanisms underlying MYC regulation by asparagine.
• To evaluate the therapeutic potential of targeting asparagine production in MYC-driven lymphoma.

Main Methods:

• Lymphoid cancer cell lines were used to study MYC expression and translation.
• Asparagine depletion was achieved through shRNA inhibition of asparagine synthetase (ASNS) and pharmacological inhibition.
• MYC mRNA and protein levels, translation rates, and degradation were analyzed.
• A MYC-driven mouse B cell lymphoma model was employed.

Main Results:

• Asparagine depletion significantly reduced MYC protein levels without affecting MYC mRNA levels.
• The reduction in MYC protein was due to inhibited translation, not increased degradation.
• The GCN2 pathway and global protein synthesis inhibition were not involved in this effect.
• Targeting ASNS or asparagine production reduced MYC protein and tumor growth in a mouse lymphoma model.

Conclusions:

• Asparagine bioavailability directly impacts MYC mRNA translation.
• This study reveals a post-transcriptional mechanism controlling MYC oncogene expression.
• Targeting asparagine metabolism presents a potential therapeutic strategy for MYC-driven cancers.