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

ABSTRACT: Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD⁺) depletion, targeting the NAD⁺ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD⁺ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD⁺ and subsequently activating the SIRT1-HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis

SUBMITTER: Suh J 

PROVIDER: S-EPMC10829737 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature