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기초과학연구원, 서울대학교

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Cell Rep. Med., December 20, 2023 | https://doi.org/10.1016/j.xcrm.2023.101342 Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axis

Jooyeon Suh,^1,2,15 Hyeonkyeong Kim,^1,2,3,15Jiyun Min,^1,2 Hyun Ju Yeon,^1,2 Martin Hemberg,⁴ Luca Scimeca,^5,6,7Ming-Ru Wu,^5,6 Hyun Guy Kang,⁸ Yi-Jun Kim,^9,10,11,* and Jin-Hong Kim ^{1,2,12,13,14,16,*}

¹Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea

²Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea

³Liflex Science, Cheongju 28160, South Korea

⁴The Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02215, USA

⁵Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

⁶Department of Immunology, Harvard Medical School, Boston, MA 02115, USA

⁷Mila, The Quebec AI Institute, Montreal, QC H2S 3H1, Canada

⁸Orthopaedic Oncology Clinic, Research Institute and Hospital, National Cancer Center, Goyang 10408, South Korea

⁹Department of Environmental Medicine, College of Medicine, Ewha Womans University, Seoul 07804, South Korea

¹⁰Department of Radiation Oncology, College of Medicine, Ewha Womans University, Seoul 07804, South Korea

¹¹Graduate Program in System Health Science and Engineering, College of Medicine, Ewha Womans University, Seoul 07804, South Korea

¹²Bio-MAX Institute, Seoul National University, Seoul 08826, South Korea

¹³Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang 25354, South Korea

¹⁴Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea

¹⁵These authors contributed equally

¹⁶Lead contact

^*Corresponding authors: correspondence to Yi-Jun Kim or Jin-Hong Kim

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 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-2α 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.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-21)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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