<br>通过靶向 SIRT1-HIF-2α 轴来解耦软骨肉瘤中的 NAD+ 代谢依赖性,Cell Reports Medicine

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通过靶向 SIRT1-HIF-2α 轴来解耦软骨肉瘤中的 NAD+ 代谢依赖性
Cell Reports Medicine ( IF 11.7 ) Pub Date : 2023-12-20 , DOI: 10.1016/j.xcrm.2023.101342
Jooyeon Suh ₁ , Hyeonkyeong Kim ₂ , Jiyun Min ₁ , Hyun Ju Yeon ₁ , Martin Hemberg ₃ , Luca Scimeca ₄ , Ming-Ru Wu ₅ , Hyun Guy Kang ₆ , Yi-Jun Kim ₇ , Jin-Hong Kim ₈

Affiliation

Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea; Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea; Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea; Liflex Science, Cheongju 28160, South Korea.
The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Mila, The Quebec AI Institute, Montreal, QC H2S 3H1, Canada.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Orthopaedic Oncology Clinic, Research Institute and Hospital, National Cancer Center, Goyang 10408, South Korea.
Department of Environmental Medicine, College of Medicine, Ewha Womans University, Seoul 07804, South Korea; Department of Radiation Oncology, College of Medicine, Ewha Womans University, Seoul 07804, South Korea; Graduate Program in System Health Science and Engineering, College of Medicine, Ewha Womans University, Seoul 07804, South Korea.
Center for RNA Research, Institute for Basic Science, Seoul 08826, South Korea; Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea; Bio-MAX Institute, Seoul National University, Seoul 08826, South Korea; Institute of Green-Bio Science and Technology, Seoul National University, Pyeongchang 25354, South Korea; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea.

软骨肉瘤是第二常见的原发性骨恶性肿瘤。尽管软骨肉瘤细胞易受烟酰胺腺嘌呤二核苷酸（NAD⁺）耗竭的影响，但由于在生物过程中的广泛影响，靶向 NAD⁺ 合成途径仍然具有挑战性。在这里，我们将 SIRT1 确立为中央介质，通过 HIF-2α 介导的转录重编程加强软骨肉瘤细胞对 NAD ⁺ 代谢的依赖性。SIRT1 敲除消除了小鼠原位移植肿瘤中软骨肉瘤的侵袭性表型。软骨肉瘤细胞通过积累 NAD⁺ 并随后激活 SIRT1-HIF-2α 轴，在葡萄糖饥饿下茁壮成长。通过 SIRT1 抑制解耦这种联系与化疗相结合可释放细胞凋亡并抑制肿瘤进展。无监督聚类分析确定了以 NAD⁺ 生物合成基因上调为特征的高危软骨肉瘤患者亚组。最后，SIRT1 抑制消除了 HIF-2α 转录活性并使软骨肉瘤细胞对阿霉素诱导的细胞毒性敏感，而不管细胞内积累 NAD⁺ 的潜在途径如何。我们提供系统级指南来制定软骨肉瘤的治疗策略。

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

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.

更新日期：2023-12-20

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