DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma
Abstract Background 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 vario...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s13578-024-01334-1 |
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| author | Ze Qian Yifan Jiang Yacong Wang Yu Li Lin Zhang Xiaofeng Xu Diyu Chen |
| author_facet | Ze Qian Yifan Jiang Yacong Wang Yu Li Lin Zhang Xiaofeng Xu Diyu Chen |
| author_sort | Ze Qian |
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| description | Abstract Background 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. Methods and results 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. Conclusions 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. Graphical Abstract |
| format | Article |
| id | doaj-art-2b7060afa8f44a8f89994117afcbed1f |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cell & Bioscience |
| spelling | doaj-art-2b7060afa8f44a8f89994117afcbed1f2025-01-19T12:40:19ZengBMCCell & Bioscience2045-37012025-01-0115111710.1186/s13578-024-01334-1DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinomaZe Qian0Yifan Jiang1Yacong Wang2Yu Li3Lin Zhang4Xiaofeng Xu5Diyu Chen6Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Gerontology, First Affiliated Hospital, Zhejiang University School of MedicineDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Pharmacology, Shaoxing People’s HospitalDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityDivision of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Background 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. Methods and results 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. Conclusions 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. Graphical Abstracthttps://doi.org/10.1186/s13578-024-01334-1ACADSHCCDNA methylationICDTumour microenvironment |
| spellingShingle | Ze Qian Yifan Jiang Yacong Wang Yu Li Lin Zhang Xiaofeng Xu Diyu Chen DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma Cell & Bioscience ACADS HCC DNA methylation ICD Tumour microenvironment |
| title | DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma |
| title_full | DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma |
| title_fullStr | DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma |
| title_full_unstemmed | DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma |
| title_short | DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma |
| title_sort | dna methylation of acads promotes immunogenic cell death in hepatocellular carcinoma |
| topic | ACADS HCC DNA methylation ICD Tumour microenvironment |
| url | https://doi.org/10.1186/s13578-024-01334-1 |
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