School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China.
School of Life Sciences, Southwest University, Beibei, Chongqing 400716, China; Chipscreen Biosciences Pharmaceutical Ltd, Chengdu, Sichuan 610041, China.
Phytomedicine. 2024 Dec;135:156024. doi: 10.1016/j.phymed.2024.156024. Epub 2024 Sep 18.
The development of cancer is accompanied by metabolic reprogramming, and the liver serves as a central hub for lipid transportation. Apigenin, a plant-derived flavonoid, demonstrates potent anticancer properties across various cancer types and exhibits promising potential as a therapeutic agent for cancer treatment. However, there are limited studies focusing on the downstream targets of apigenin. Moreover, there are few reports on the impact of apigenin in lipid metabolism within liver cancer cells.
The objective is to elucidate the metabolic mechanism underlying the inhibitory effect of apigenin on liver cancer progression, search for downstream targets and provide reliable data support for the clinical trials of apigenin.
Anticancer effects of apigenin were detected at cellular and molecular levels in vitro, and downstream targets of apigenin, especially metabolic pathway genes, were analyzed by transcriptome. Next, the downstream target of apigenin was verified and the biological function of the downstream target was examined. Finally, the downstream target of apigenin was further verified by restoring target gene expression.
Cellular molecular experiments showed that Apigenin inhibited the proliferation, migration, invasion and lipid metabolism of hepatocellular carcinoma (HCC) cells. Transcriptome analysis showed apigenin widely regulates histone demethylase, particularly histone H3K4 lysine demethylase 1A (KDM1A). Apigenin treatment inhibited the expression of KDM1A protein and mRNA levels in liver cancer cells, molecular docking predicted the interaction between apigenin and KDM1A. Furthermore, downregulation KDM1A inhibited the proliferation and lipid metabolism of HCC cells, in the same way, overexpressing KDM1A promoted proliferation of HCC cells. Finally, restoring KDM1A expression partially attenuated the effects of apigenin on lipid metabolism in HCC cells.
In conclusion, our study provides compelling evidence that apigenin inhibits liver cancer progression and elucidates its mechanism of action in regulating lipid metabolism. Specifically, we find that apigenin suppresses the progression of HCC cells by downregulating genes involved in lipid metabolism. Additionally, our results indicate that KDM1A acts as a downstream target of apigenin in the inhibition of lipid metabolism in HCC. These findings offer experimental support for the potential use of apigenin as a therapeutic agent for liver cancer, highlighting its relevance in future clinical applications.
癌症的发展伴随着代谢重编程，而肝脏是脂质运输的中心枢纽。芹菜素是一种植物衍生的类黄酮，在多种癌症类型中表现出强大的抗癌特性，并显示出作为癌症治疗药物的有前途的潜力。然而，针对芹菜素的下游靶点的研究有限。此外，关于芹菜素在肝癌细胞内脂质代谢中的作用的报道很少。
阐明芹菜素抑制肝癌进展的代谢机制，寻找下游靶点，并为芹菜素的临床试验提供可靠的数据支持。
在体外从细胞和分子水平检测芹菜素的抗癌作用，并通过转录组分析芹菜素的下游靶点，特别是代谢途径基因。接下来，验证芹菜素的下游靶点，并研究下游靶点的生物学功能。最后，通过恢复靶基因表达进一步验证芹菜素的下游靶点。
细胞分子实验表明，芹菜素抑制肝癌细胞的增殖、迁移、侵袭和脂质代谢。转录组分析表明，芹菜素广泛调节组蛋白去甲基酶，特别是组蛋白 H3K4 赖氨酸去甲基酶 1A（KDM1A）。芹菜素处理抑制肝癌细胞中 KDM1A 蛋白和 mRNA 水平的表达，分子对接预测了芹菜素与 KDM1A 之间的相互作用。此外，下调 KDM1A 抑制 HCC 细胞的增殖和脂质代谢，同样，过表达 KDM1A 促进 HCC 细胞的增殖。最后，恢复 KDM1A 的表达部分减弱了芹菜素对 HCC 细胞脂质代谢的影响。
综上所述，我们的研究提供了令人信服的证据，表明芹菜素抑制肝癌的进展，并阐明了它在调节脂质代谢中的作用机制。具体来说，我们发现芹菜素通过下调参与脂质代谢的基因来抑制 HCC 细胞的进展。此外，我们的结果表明 KDM1A 作为芹菜素抑制 HCC 细胞脂质代谢的下游靶点。这些发现为芹菜素作为肝癌治疗药物的潜在用途提供了实验支持，突出了其在未来临床应用中的相关性。
