Decoupling NAD⁺ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Chondrosarcoma is a common primary bone cancer.
• Targeting nicotinamide adenine dinucleotide (NAD+) metabolism is difficult due to its broad biological roles.
• Chondrosarcoma cells show vulnerability to NAD+ depletion.

Purpose of the Study:

• Investigate the role of SIRT1 in chondrosarcoma NAD+ metabolism.
• Determine the therapeutic potential of targeting the SIRT1-HIF-2α axis in chondrosarcoma.
• Identify patient subgroups that may benefit from SIRT1 inhibition.

Main Methods:

• SIRT1 knockdown in orthotopic mouse models.
• Analysis of NAD+ accumulation under glucose starvation.
• Unsupervised clustering of patient data based on NAD+ biosynthesis genes.
• Assessment of SIRT1 inhibition in combination with doxorubicin.

Main Results:

• SIRT1 knockdown eliminated aggressive chondrosarcoma phenotypes in vivo.
• Chondrosarcoma cells activate the SIRT1-HIF-2α axis under glucose starvation.
• SIRT1 inhibition induced apoptosis and suppressed tumor progression.
• A high-risk patient subgroup with upregulated NAD+ biosynthesis genes was identified.
• SIRT1 inhibition sensitized cells to doxorubicin, regardless of NAD+ accumulation pathways.

Conclusions:

• SIRT1 is a key mediator of chondrosarcoma's dependency on NAD+ metabolism via HIF-2α.
• Targeting SIRT1 offers a promising therapeutic strategy for chondrosarcoma, potentially enhancing chemotherapy.
• System-level guidelines for developing chondrosarcoma therapies are proposed.