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Updated: Jun 3, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA methylation of ACADS promotes immunogenic cell death in hepatocellular carcinoma
Ze Qian1, Yifan Jiang1, Yacong Wang2
1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
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.
Insights
Acyl-CoA dehydrogenase short-chain (ACADS) functions as a tumor suppressor in hepatocellular carcinoma (HCC). Its methylation predicts survival and suggests ACADS as a target for HCC immunotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Altered cellular metabolism is a hallmark of cancer.
- Acyl-CoA dehydrogenase short-chain (ACADS), a lipid metabolism regulator, is implicated in cancer.
- DNA methylation frequently silences ACADS in malignancies, but its role in hepatocellular carcinoma (HCC) is unclear.
Purpose of the Study:
- To investigate the role of ACADS in HCC pathogenesis.
- To identify specific epigenetic modifications affecting ACADS in HCC.
- To evaluate ACADS as a prognostic biomarker and therapeutic target in HCC.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) RNA sequencing data for ACADS expression and methylation in HCC.
- Identification and validation of CpG island methylation sites in the ACADS promoter (cg08618068, termed ACADS MS-2).
- In vivo and in vitro experiments to assess the functional impact of ACADS methylation and overexpression on HCC cell behavior and immunogenic cell death (ICD).
Main Results:
- ACADS was found to be downregulated and hypermethylated in HCC tumors.
- Methylation at ACADS MS-2 was associated with poorer patient survival.
- ACADS overexpression suppressed HCC cell proliferation, migration, and invasion, and promoted ICD by upregulating calreticulin.
- A nomogram incorporating ACADS methylation levels demonstrated predictive performance for patient survival.
Conclusions:
- ACADS functions as a tumor suppressor in HCC.
- ACADS methylation is a significant prognostic factor for HCC patients.
- The correlation between ACADS and ICD highlights its potential as a target for HCC immunotherapy.
