USP15通过抑制透明细胞肾细胞癌中的铜死亡来稳定c-Myc，从而驱动舒尼替尼耐药
USP15 stabilizes c-Myc to drive sunitinib resistance by suppressing cuproptosis in clear cell renal cell carcinoma.
摘要(中文译文)
铜死亡（cuproptosis）是近年来被阐明的一种由铜蓄积触发的线粒体依赖性细胞死亡形式，其在透明细胞肾细胞癌（ccRCC）及舒尼替尼耐药中的作用尚未被探索。在此，我们发现去泛素化酶USP15抑制铜死亡并驱动ccRCC中的舒尼替尼耐药。机制上，USP15通过K143和K289位点的K48连接去泛素化稳定c-Myc，导致PDK1、PDK3和PDK4转录上调，进而抑制DLAT表达和丙酮酸脱氢酶，从而赋予对铜死亡的抵抗。相反，E3连接酶MYCBP2促进c-Myc的K48连接泛素化及降解，拮抗USP15的功能。舒尼替尼处理可诱导铜死亡特征，而耐药细胞中USP15上调则抑制了这些效应。敲低USP15或使用伊利司莫（ES）-Cu/双硫仑（DSF）-Cu可在体外和体内恢复舒尼替尼敏感性，且无全身毒性。总之，我们的研究结果确定USP15是铜死亡和舒尼替尼耐药的关键调控因子，并强调激活铜死亡是克服ccRCC中酪氨酸激酶抑制剂（TKI）耐药的一种有前景的策略。
Abstract
Cuproptosis, a recently characterized form of mitochondrial-dependent cell death triggered by copper accumulation, remains unexplored in clear cell renal cell carcinoma (ccRCC) and sunitinib resistance. Here, we reveal that the deubiquitinase USP15 suppressed cuproptosis and drove sunitinib resistance in ccRCC. Mechanistically, USP15 stabilized c-Myc through K48-linked deubiquitination at K143 and K289, leading to transcriptional upregulation of PDK1, PDK3, and PDK4 and subsequent repression of DLAT expression and pyruvate dehydrogenase, thereby conferring resistance to cuproptosis. Conversely, the E3 ligase MYCBP2 promoted K48-linked ubiquitination and degradation of c-Myc, antagonizing USP15 function. Sunitinib treatment induced features of cuproptosis, while USP15 upregulation in resistant cells suppressed these effects. USP15 depletion or elesclomol (ES)-Cu/disulfiram (DSF)-Cu restored sunitinib sensitivity both in vitro and vivo without systemic toxicity. Collectively, our findings identify USP15 as a critical regulator of cuproptosis and sunitinib resistance and highligh cuproptosis activation as a promising strategy to overcome tyrosine kinase inhibitor (TKI) resistance in ccRCC.
如何引用
AMA
Yujie Chen, Shiyu Huang, Lei Wang, Zhiyuan Yao, Shujie Fu, Juncheng Hu, et al. USP15 stabilizes c-Myc to drive sunitinib resistance by suppressing cuproptosis in clear cell renal cell carcinoma.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117328.
APA
Yujie Chen, Shiyu Huang, Lei Wang, Zhiyuan Yao, Shujie Fu, Juncheng Hu, et al (2026). USP15 stabilizes c-Myc to drive sunitinib resistance by suppressing cuproptosis in clear cell renal cell carcinoma.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117328
GB/T 7714
Yujie Chen, Shiyu Huang, Lei Wang, Zhiyuan Yao, Shujie Fu, Juncheng Hu, et al. USP15 stabilizes c-Myc to drive sunitinib resistance by suppressing cuproptosis in clear cell renal cell carcinoma.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117328.
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