The mechanisms underlying cancer metastasis remain poorly understood. Here, we report that TFAM deficiency rapidly and stably induced spontaneous lung metastasis in mice with liver cancer. Interestingly, unexpected polymerization of nuclear actin was observed in TFAM-knockdown HCC cells when cytoskeleton was examined. Polymerization of nuclear actin is causally linked to the high-metastatic ability of HCC cells by modulating chromatin accessibility and coordinating the expression of genes associated with extracellular matrix remodeling, angiogenesis, and cell migration. Mechanistically, TFAM deficiency blocked the TCA cycle and increased the intracellular malonyl-CoA levels. Malonylation of mDia2, which drives actin assembly, promotes its nuclear translocation. Importantly, inhibition of malonyl-CoA production or nuclear actin polymerization significantly impeded the spread of HCC cells in mice. Moreover, TFAM was significantly downregulated in metastatic HCC tissues and was associated with overall survival and time to tumor recurrence of HCC patients. Taken together, our study connects mitochondria to the metastasis of human cancer via uncovered mitochondria-to-nucleus retrograde signaling, indicating that TFAM may serve as an effective target to block HCC metastasis.

中文翻译：

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TFAM 丢失会在 mDia2 丙二酰化后诱导核肌动蛋白组装，从而促进肝癌转移。

癌症转移的潜在机制仍然知之甚少。在这里，我们报告了 TFAM 缺陷在肝癌小鼠中快速稳定地诱导自发性肺转移。有趣的是，当检查细胞骨架时，在 TFAM 敲低的 HCC 细胞中观察到意外的核肌动蛋白聚合。核肌动蛋白的聚合通过调节染色质可及性和协调与细胞外基质重塑、血管生成和细胞迁移相关的基因表达，与 HCC 细胞的高转移能力存在因果关系。从机制上讲，TFAM 缺乏会阻断 TCA 循环并增加细胞内丙二酰辅酶 A 水平。驱动肌动蛋白组装的 mDia2 的丙二酰化促进其核转位。重要的，抑制丙二酰辅酶 A 的产生或核肌动蛋白聚合显着阻碍了 HCC 细胞在小鼠中的扩散。此外，TFAM 在转移性 HCC 组织中显着下调，并且与 HCC 患者的总生存期和肿瘤复发时间相关。总之，我们的研究通过未发现的线粒体到细胞核逆行信号将线粒体与人类癌症的转移联系起来，表明 TFAM 可以作为阻止 HCC 转移的有效靶点。