肝细胞癌(HCC)是肝脏的原发性恶性肿瘤。c-Myc是临床上最常见的癌基因之一,在HCC中经常发现c-Myc的扩增水平。组蛋白脱乙酰酶抑制剂(HDACi),例如曲古抑菌素A(TSA),对肝癌的治疗有着巨大的希望。然而,TSA治疗c-Myc诱导的HCC的潜力和机制尚不清楚。在这项研究中,我们研究了TSA治疗对c-Myc诱导的小鼠HCC模型的影响。TSA治疗延迟肝癌的发展,和肝功能指标如ALT,AST,肝脏重量比,和脾脏重量比证明了TSA治疗的有效性。油红染色进一步证明TSA减弱了小鼠HCC组织中的脂质积累。通过mRNA测序,我们确定TSA主要影响细胞周期和脂肪酸降解基因,醇脱氢酶4(ADH4)可能是下游的核心分子靶标。QPCR,免疫组织化学,和蛋白质印迹分析显示,在体外和体内TSA处理后,ADH4表达被c-Myc抑制并恢复。此外,我们观察到总NAD+和NADH的水平,NAD+,NAD+/NADH,c-Myc转染肝细胞后ATP浓度升高,TSA干预后ATP浓度降低。磷酸化蛋白激酶B(p-AKT)和p-mTOR的水平被确定为TSA调节的目标。它们控制着ADH4的表达和总NAD+和NADH的下游调节,NAD+,NAD+/NADH,和ATP浓度。总的来说,我们的研究提示TSA通过AKT-mTOR-ADH4通路对c-Myc诱导的HCC有治疗作用.这些发现为使用TSA治疗HCC提供了有价值的见解,并阐明了所涉及的潜在分子机制。
Hepatocellular carcinoma (HCC) is the primary malignant tumor of the liver. c-Myc is one of the most common oncogenes in clinical settings, and amplified levels of c-Myc are frequently found in HCC. Histone deacetylase inhibitors (HDACi), such as Trichostatin A (TSA), hold enormous promise for the treatment of HCC. However, the potential and mechanism of TSA in the treatment of c-Myc-induced HCC are unclear. In this study, we investigated the effects of TSA treatment on a c-Myc-induced HCC model in mice. TSA treatment delayed the development of HCC, and liver function indicators such as ALT, AST, liver weight ratio, and spleen weight ratio demonstrated the effectiveness of TSA treatment. Oil red staining further demonstrated that TSA attenuated lipid accumulation in the HCC tissues of mice. Through mRNA sequencing, we identified that TSA mainly affected cell cycle and fatty acid degradation genes, with alcohol dehydrogenase 4 (ADH4) potentially being the core molecular downstream target. QPCR, immunohistochemistry, and western blot analysis revealed that ADH4 expression was repressed by c-Myc and restored after TSA treatment both in vitro and in vivo. Furthermore, we observed that the levels of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration increased after c-Myc transfection in liver cells but decreased after TSA intervention. The levels of phosphorylated protein kinase B (p-AKT) and p-mTOR were identified as targets regulated by TSA, and they governed the ADH4 expression and the downstream regulation of total NAD+ and NADH, NAD+, NAD+/NADH, and ATP concentration. Overall, our study suggests that TSA has a therapeutic effect on c-Myc-induced HCC through the AKT-mTOR-ADH4 pathway. These findings provide valuable insights into the potential treatment of HCC using TSA and shed light on the underlying molecular mechanisms involved.