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Decoupling NAD plus metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2a axis
- Title
- Decoupling NAD plus metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2a axis
- Authors
- Suh, Jooyeon; Kim, Hyeonkyeong; Min, Jiyun; Yeon, Hyun Ju; Hemberg, Martin; Scimeca, Luca; Wu, Ming-Ru; Kang, Hyun Guy; Kim, Yi-Jun; Kim, Jin-Hong
- Ewha Authors
- 김이준
- SCOPUS Author ID
- 김이준
- Issue Date
- 2024
- Journal Title
- CELL REPORTS MEDICINE
- ISSN
- 2666-3791
- Citation
- CELL REPORTS MEDICINE vol. 5, no. 1
- Publisher
- CELL PRESS
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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-2a-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-2a axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high -risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2a transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system -level guidelines to develop therapeutic strategies for chondrosarcomas.
- DOI
- 10.1016/j.xcrm.2023.101342|http://dx.doi.org/10.1016/j.xcrm.2023.101342
- Appears in Collections:
- 의과대학 > 의학과 > Journal papers
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