<br>天然产物fargesin通过靶向PKM2干扰H3组蛋白乳酰化抑制非小细胞肺癌发生,Biofactors

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天然产物fargesin通过靶向PKM2干扰H3组蛋白乳酰化抑制非小细胞肺癌发生
Biofactors ( IF 5.0 ) Pub Date : 2023-12-27 , DOI: 10.1002/biof.2031
Zizhang Guo ₁ , Yeqing Tang ₁ , Shunshun Wang ₂ , Yuming Huang ₁ , Qingjia Chi ₃ , Kang Xu _{2,

4} , Lei Xue ₁

Affiliation

非小细胞肺癌（NSCLC）是最常见的恶性肿瘤之一。迫切需要寻找更有效的抑制NSCLC的药物。 Fargesin (FGS) 已被证明具有抗肿瘤作用；但其功效和抑制NSCLC的分子机制尚不清楚。在此，我们通过 CCK8 和 EdU 测定以及体外 A549 细胞和体内裸鼠肿瘤移植模型的细胞周期分析研究了 FGS 对 NSCLC 的抑制作用。 FGS (10–50 μM) 显着抑制细胞增殖并下调 CDK1 和 CCND1 的表达水平。转录组分析表明FGS调节细胞代谢过程途径。 FGS 处理后的差异代谢物在糖酵解和丙酮酸途径中富集。采用细胞代谢测定法评价A549细胞的耗氧率（OCR）、细胞外酸化率（ECAR）。 FGS 还抑制细胞乳酸的产生以及 LDHA、LDHB、PKM2 和 SLC2A1 的表达。这些基因被鉴定为肺癌的重要癌基因，并通过分子对接模拟证实了它们与FGS的结合。值得注意的是，过表达和基因沉默实验表明 PKM2 是 FGS 抗肿瘤发生的分子靶点。此外，与肿瘤发生相关的 H3 组蛋白乳酰化受到 FGS 治疗的抑制。总之，FGS 通过靶向 PKM2 抑制 A549 NSCLC 细胞中的有氧糖酵解和 H3 组蛋白乳酰化信号通路。这些发现提供了 FGS 在 NSCLC 中的治疗潜力的证据。

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Natural product fargesin interferes with H3 histone lactylation via targeting PKM2 to inhibit non-small cell lung cancer tumorigenesis

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. There is an urgent need to find more effective drugs that inhibit NSCLC. Fargesin (FGS) has demonstrated anti-tumor effects; however, its efficacy and the molecular mechanism of inhibiting NSCLC are unclear. Herein, we investigated FGS’ inhibitory effects on NSCLC by CCK8 and EdU assays and cell cycle analysis of A549 cells in vitro and in a nude mouse tumor transplantation model in vivo. FGS (10–50 μM) significantly inhibited cell proliferation and down-regulated expression levels of CDK1 and CCND1. Transcriptomic analysis showed that FGS regulated the cell metabolic process pathway. Differential metabolites with FGS treatment were enriched in glycolysis and pyruvate pathways. Cell metabolism assay were used to evaluate the oxygen consumption rate (OCR), Extracellular acidification rate (ECAR) in A549 cells. FGS also inhibited the production of cellular lactate and the expression of LDHA, LDHB, PKM2, and SLC2A1. These genes were identified as important oncogenes in lung cancer, and their binding to FGS was confirmed by molecular docking simulation. Notably, the over-expression and gene silencing experiments signified PKM2 as the molecular target of FGS for anti-tumorigenesis. Moreover, the H3 histone lactylation, were correlated with tumorigenesis, were inhibited with FGS treatment. Conclusively, FGS inhibited the aerobic glycolytic and H3 histone lactylation signaling pathways in A549 NSCLC cells by targeting PKM2. These findings provide evidence of the therapeutic potential of FGS in NSCLC.

更新日期：2023-12-27

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