Qian Ze, Jiang Yifan, Wang Yacong, Li Yu, Zhang Lin, Xu Xiaofeng, Chen Diyu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
Department of Gerontology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China.
Cell Biosci. 2025 Jan 12;15(1):3. doi: 10.1186/s13578-024-01334-1.
Altered metabolism has become an important characteristic of cancer, and acyl-CoA dehydrogenase short-chain (ACADS), a regulator of lipid synthesis, is involved in carcinogenesis-associated metabolic pathways. DNA methylation is an important mechanism for silencing ACADS in various malignancies. However, the specific role of ACADS in hepatocellular carcinoma (HCC) pathogenesis remains poorly understood.
Using RNA sequencing data from different tumours in The Cancer Genome Atlas database, we observed that ACADS was downregulated and hypermethylated in HCC. Three potential CpG island sites (cg01535453, cg08618068, and cg10174836) were identified in the ACADS promoter. Through in vivo and in vitro experiments, we confirmed that cg08618068 was methylated in HCC. We defined this site as ACADS methylation site-2 (ACADS MS-2). Methylation of ACADS MS-2 was associated with worse survival, and mutation of MS-2 increased ACADS mRNA levels in five HCC cell lines. Sustained overexpression of ACADS not only suppressed the proliferation, migration, and invasion of HCC cells but also promoted immunogenic cell death (ICD) via the upregulation of calreticulin. Subsequently, we established a specific nomogram based on ACADS methylation levels to evaluate the 3- and 5-year overall survival rates of patients with HCC who underwent surgical resection.
Our work clarified that ACADS acts as a putative tumour suppressor in HCC and confirmed that a nomogram including ACADS methylation had good predictive performance in HCC. We also discovered a correlation between ACADS and ICD, suggesting that ACADS is an essential target for immunotherapy in HCC.
代谢改变已成为癌症的一个重要特征，而脂酰辅酶A脱氢酶短链（ACADS）作为脂质合成的调节因子，参与了与致癌作用相关的代谢途径。DNA甲基化是各种恶性肿瘤中使ACADS沉默的重要机制。然而，ACADS在肝细胞癌（HCC）发病机制中的具体作用仍知之甚少。
利用癌症基因组图谱数据库中不同肿瘤的RNA测序数据，我们观察到ACADS在HCC中表达下调且发生了高甲基化。在ACADS启动子中鉴定出三个潜在的CpG岛位点（cg01535453、cg08618068和cg10174836）。通过体内和体外实验，我们证实cg08618068在HCC中发生了甲基化。我们将该位点定义为ACADS甲基化位点2（ACADS MS-2）。ACADS MS-2的甲基化与较差的生存率相关，并且MS-2的突变在五种HCC细胞系中增加了ACADS mRNA水平。ACADS的持续过表达不仅抑制了HCC细胞的增殖、迁移和侵袭，还通过上调钙网蛋白促进了免疫原性细胞死亡（ICD）。随后，我们基于ACADS甲基化水平建立了一个特定的列线图，以评估接受手术切除的HCC患者的3年和5年总生存率。
我们的工作阐明了ACADS在HCC中作为一种假定的肿瘤抑制因子发挥作用，并证实包含ACADS甲基化的列线图在HCC中具有良好的预测性能。我们还发现了ACADS与ICD之间的相关性，表明ACADS是HCC免疫治疗的一个重要靶点。
