Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity. We ascribed these ATGL-downstream events to the activity of the tumor-suppressor p53, whose protein levels-but not transcript-were upregulated upon ATGL overexpression. The role of p53 was further assessed by abrogation of the ATGL-mediated effects upon p53 silencing or in p53-null hepatocarcinoma Hep3B cells. Furthermore, we provided insights on the molecular mechanisms governed by ATGL in HCC cells, identifying a new PPAR-α/p300 axis responsible for p53 acetylation/accumulation. Finally, we highlighted that ATGL levels confer different susceptibility of HCC cells to common therapeutic drugs, with ATGL overexpressing cells being more resistant to glycolysis inhibitors (e.g., 2-deoxyglucose and 3-bromopyruvate), compared to genotoxic compounds. Collectively, our data provide evidence for a previously uncovered tumor-suppressor function of ATGL in HCC, with the outlined molecular mechanisms shedding light on new potential targets for anticancer therapy.

中文翻译：

---

迫使肝癌细胞中的ATGL表达通过PPAR-α/ p300介导的p53乙酰化作用进行糖酵解。

代谢重编程是癌细胞的一个典型特征，旨在维持高能量需求和增殖率。在这里，我们报告了在人类和小鼠诱发的肝细胞癌（HCC）中降低甘油三酸酯脂肪酶（ATGL）（甘油三酸酯水解的第一种酶和限速酶）表达的明确证据。我们确定代谢重排是肝癌来源的细胞系中ATGL过表达的主要结果。实际上，ATGL降低了葡萄糖的摄取/利用和细胞增殖，同时增加了脂肪酸的氧化代谢和增强的线粒体能力。我们将这些ATGL下游事件归因于肿瘤抑制因子p53的活性，后者在ATGL过表达时其蛋白水平（而非转录本）被上调。通过废除ATGL介导的对p53沉默或在p53无效的肝癌Hep3B细胞中的作用，进一步评估了p53的作用。此外，我们提供了关于ATGL在HCC细胞中控制的分子机制的见解，从而确定了负责p53乙酰化/积累的新PPAR-α/ p300轴。最后，我们强调了ATGL水平赋予普通治疗药物不同的HCC细胞敏感性，与遗传毒性化合物相比，ATGL过表达的细胞对糖酵解抑制剂（例如2-脱氧葡萄糖和3-溴丙酮酸盐）的耐药性更高。总的来说，我们的数据为先前未发现的ATGL在HCC中的肿瘤抑制功能提供了证据，其概述的分子机制为抗癌治疗的新潜在靶标提供了线索。