CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells.

IF 5.1 1区生物学 Q1 BIOLOGY Communications Biology Pub Date : 2025-02-16 DOI:10.1038/s42003-025-07720-w

Yaqin Zhu, Shuting Chen, Hong Su, Yaning Meng, Chen Zang, Panjiao Ning, Lele Hu, Huanjie Shao

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Abstract

Cancer stem cells (CSCs) play crucial roles in cancer progression, immune evasion, drug resistance, and recurrence. Understanding the mechanisms behind CSCs generation and stemness maintenance is vital for early cancer diagnosis and treatment. Here, we unveil that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer stem cells (OCSCs) and is essential for maintaining stemness by regulating lipid desaturation. Studies confirmed that CPT1A enhances SREBP1 activation, upregulating SCD1 expression, and promoting lipid desaturation in OCSCs. Mechanistic studies reveal that CPT1A promotes succinylation of mitochondrial fission factor (MFF) through its lysine succinyltransferase (LSTase) activity, crucial for mitochondria-associated membranes formation and SREBP1 activation. Inhibiting CPT1A's LSTase activity with Glyburide reduces OCSCs' stemness and enhances cisplatin's anti-tumor effects against ovarian cancer in vitro and in vivo. Together, our studies highlight the significance of CPT1A's LSTase activity in maintaining OCSCs' stemness, offering potential targets and therapeutic strategies for ovarian cancer treatment.

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cpt1a介导的MFF琥珀酰化促进卵巢癌干细胞的干细胞维持。

肿瘤干细胞（CSCs）在肿瘤进展、免疫逃逸、耐药和复发中起着至关重要的作用。了解CSCs生成和干细胞维持背后的机制对早期癌症诊断和治疗至关重要。在这里，我们揭示了肉碱棕榈酰基转移酶1A （CPT1A）在卵巢癌干细胞（OCSCs）中高度表达，并且通过调节脂质去饱和来维持干细胞性。研究证实，CPT1A可增强SREBP1的激活，上调SCD1的表达，促进OCSCs的脂质去饱和。机制研究表明，CPT1A通过其赖氨酸琥珀酰转移酶（LSTase）活性促进线粒体裂变因子（MFF）的琥珀酰化，这对于线粒体相关膜的形成和SREBP1的激活至关重要。格列本脲抑制CPT1A的LSTase活性，降低OCSCs的干性，增强顺铂体外和体内抗卵巢癌的抗肿瘤作用。总之，我们的研究强调了CPT1A的LSTase活性在维持OCSCs的干性中的重要性，为卵巢癌治疗提供了潜在的靶点和治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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penicillin-streptomycin

来源期刊

Communications Biology Medicine-Medicine (miscellaneous)

CiteScore

8.60

自引率

1.70%

发文量

1233

审稿时长

13 weeks

期刊介绍： Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.