Glutamine Deprivation Triggers Tribbles Homolog 3 Dependent G-Quadruplex Resolution to Maintain DNA Repair and Tumor...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Glutamine is vital for tumor growth, but therapies targeting its metabolism face resistance.
• Hepatocellular carcinoma (HCC) cells exhibit adaptive resistance to glutamine deprivation.
• Understanding resistance mechanisms is crucial for developing effective HCC treatments.

Purpose of the Study:

• Identify key mediators of metabolic adaptation in HCC cells under glutamine limitation.
• Investigate the role of the pseudokinase TRIB3 in cellular response to glutamine scarcity.
• Explore the TRIB3-DDX5-G4 DNA axis as a potential therapeutic target in HCC.

Main Methods:

• Investigated TRIB3 expression and function in HCC cells under glutamine deprivation.
• Utilized c-Jun knockdown and TRIB3/DDX5 depletion experiments.
• Analyzed DNA damage, G-quadruplex DNA (G4-DNA) structures, and DNA damage repair (DDR) pathways.
• Performed in vivo studies using HCC xenografts in mice on glutamine-deficient diets.
• Correlated TRIB3 expression with clinical HCC patient data.

Main Results:

• TRIB3 is upregulated under glutamine deprivation, safeguarding DNA repair fidelity.
• TRIB3 and DDX5 form a complex that resolves G4-DNA structures.
• Depletion of TRIB3 or DDX5 increases G4-DNA accumulation, DNA damage, and suppresses DDR pathways, including homologous recombination (HR).
• TRIB3-DDX5 prevents G4-DNA mediated suppression of BRCA1 and RAD51AP1 transcription.
• TRIB3 silencing inhibits HCC xenograft growth and increases apoptosis under glutamine deficiency.
• TRIB3 is overexpressed in HCC and linked to poor prognosis.

Conclusions:

• The TRIB3-DDX5-G4 DNA axis is a critical mediator of metabolic adaptation and DNA repair in HCC.
• This axis represents a promising therapeutic target for HCC and other TRIB3-high cancers.
• Targeting TRIB3 could overcome resistance to therapies targeting glutamine metabolism.