Mitochondrial transcription factor A (TFAM), which is required for mitochondrial DNA (mtDNA) transcription, has been linked to metabolic changes that contribute to tumorigenesis and chemoresistance. In this work, we investigated the expression pattern and role of TFAM in hepatocellular carcinoma (HCC). TFAM expression level is similar in 18 out of 20 paired normal liver and HCC tissues with only 2 HCC tissues showing 1.8-fold increase in TFAM. Similar phenomenon was observed in HCC cell lines compared to normal liver lines. Interestingly, TFAM expression is upregulated in resistant HCC cells regardless of the differential TFAM expression level in their parental lines and mechanism of resistance. TFAM depletion led to inhibition of growth and survival but not migration, and sensitization to doxorubicin and sorafenib treatment, through AMPK activation, reduction of nucleoside triphosphates and mitochondrial respiration in HCC cells. In addition, we demonstrated that resistant HCC cell lines were more sensitive to TFAM inhibition than parental lines, and this might be due to the increased mitochondrial biogenesis in resistant HCC cell lines. Our work reveals the preferential role of TFAM in HCC cell response to standard of care drugs, which suggests a potential sensitizing therapeutic target for HCC treatment.

线粒体DNA（mtDNA）转录所需的线粒体转录因子A（TFAM）已与有助于肿瘤发生和化学抗性的代谢变化相关。在这项工作中，我们调查了TFAM在肝细胞癌（HCC）中的表达模式和作用。在20个配对的正常肝和HCC组织中，有18个组织的TFAM表达水平相似，只有2个HCC组织显示TFAM增加了1.8倍。与正常肝细胞系相比，在HCC细胞系中观察到类似现象。有趣的是，无论其亲本系中的TFAM表达水平是否不同，以及抗性机制如何，在耐药HCC细胞中TFAM表达都会上调。TFAM消耗导致抑制生长和存活，但不能迁移，对阿霉素和索拉非尼治疗敏感，通过AMPK激活，减少三磷酸核苷和HCC细胞中的线粒体呼吸。此外，我们证明了抗性HCC细胞系对TFAM抑制作用比亲本系更为敏感，这可能是由于抗性HCC细胞系线粒体生物发生增加所致。我们的工作揭示了TFAM在HCC细胞对护理药物标准的反应中的优先作用，这暗示了HCC治疗的潜在敏化治疗靶点。