Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1
Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1
复制标题
GCN5L1逆行调控肝癌线粒体分裂和上皮向间质转化
DOI：
10.1038/s41388-023-02621-w
复制
发表时间：
2023-02-09
期刊：
影响因子：
8
通讯作者：
Zhu, Lu
中科院分区：
文献类型：
--
作者：
Han, Linmeng;Zhang, Chunyu;Zhu, Lu
代谢再编程对于支持癌细胞的生长和运动以及决定细胞的命运至关重要。线粒体蛋白乙酰化调节线粒体代谢，线粒体代谢与癌细胞迁移和侵袭有关。线粒体蛋白乙酰化在癌细胞迁移中的功能作用尚不清楚。氨基酸合成总控5样蛋白-1(GCN5L1)作为线粒体蛋白乙酰化的调节因子，在小鼠肝脏的代谢重编程中发挥作用。在本研究中，我们发现GCN5L1在转移性肝癌组织中的表达显著降低。GCN5L1的缺失通过增强脂肪酸氧化(FAO)促进活性氧物种(ROS)的产生，随后激活细胞ERK和DRp1促进线粒体分裂和上皮细胞向间充质细胞的转变(EMT)以促进细胞迁移。此外，棕榈酸酯和肉碱刺激的FAO促进线粒体分裂和EMT基因表达，从而激活肝癌细胞的迁移。另一方面，粮农组织的产物细胞乙酰-辅酶A水平增加，促进了肝癌细胞的迁移。综上所述，我们的发现揭示了GCN5L1在肝癌中的转移抑制作用以及潜在的机制，也为粮农组织逆行控制肝癌转移提供了证据。
Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.