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CHD5 a tumour suppressor is epigenetically silenced in hepatocellular carcinoma
Rui Zhao1, Nisha Wang, Haili Huang
1Institute of Molecular Biology, Southern Medical University, Guangzhou, China.
Background:
Chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a potent tumour suppressor by acting as a master regulator of a tumour-suppressive network. Its inactivation resulted from aberrant methylation in the promoter occurs in several types of human malignancy and is associated with malignant tumour behaviour. In human hepatocellular carcinoma (HCC), CHD5 gene expression, methylation status and tumour-suppressive function have not been elucidated.
Aims:
In this study, we focused on the epigenetic modification and tumour-suppressive mechanism of CHD5 gene in HCC.
Methods:
CHD5 expression in nine HCC cell lines and 30 pairs of HCC specimens and adjacent non-cancerous tissues were analysed by quantitative reverse transcription PCR and Western blotting. Methylation-specific sequencing and methylation-specific PCR were performed to examine DNA methylation status of the CHD5 promoter in HCC cell lines and samples. The effect of CHD5 restoration on proliferation, colony formation, senescence, apoptosis and tumourigenicity were examined.
Results:
CHD5 expression was sinificantly down-regulated in HCC cell lines and tissues examined, and the -841 to -470 region of CHD5 promoter was hypermethylated in these samples. Treatment with DNA methyltransferase inhibitor 5-aza-2-deoxycytidine resulted in a striking regional demethylation of the -841 to -470 region of CHD5 promoter and an increase in CHD5 expression. The restoration of CHD5 expression inhibited tumour cell proliferation, colony formation and tumourigenicity and caused cellular senescence.
Conclusions:
Our findings demonstrate that CHD5 is a potential tumour suppressor gene epigenetically silenced in HCC.
Insights
Chromodomain helicase DNA binding protein 5 (CHD5) acts as a tumor suppressor. In hepatocellular carcinoma (HCC), CHD5 is epigenetically silenced by promoter hypermethylation, inhibiting tumor growth and promoting senescence.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Chromodomain helicase DNA binding protein 5 (CHD5) is a known tumor suppressor regulating a critical network.
- Aberrant promoter methylation inactivates CHD5 in various malignancies, correlating with tumor progression.
- The role of CHD5 in hepatocellular carcinoma (HCC), including its expression, methylation, and tumor-suppressive function, remained unclear.
Purpose of the Study:
- To investigate the epigenetic regulation and tumor-suppressive mechanisms of the CHD5 gene in HCC.
- To elucidate the role of CHD5 in HCC development and progression.
Main Methods:
- Quantitative reverse transcription PCR and Western blotting were used to analyze CHD5 expression in HCC cell lines and tissues.
- Methylation-specific sequencing and PCR assessed CHD5 promoter DNA methylation status.
- Functional assays examined the impact of CHD5 restoration on HCC cell proliferation, colony formation, senescence, apoptosis, and tumorigenicity.
Main Results:
- CHD5 expression was significantly downregulated in HCC cell lines and specimens.
- The -841 to -470 region of the CHD5 promoter was hypermethylated in HCC samples.
- Treatment with 5-aza-2-deoxycytidine induced demethylation and restored CHD5 expression, inhibiting tumor cell proliferation, colony formation, and tumorigenicity, while inducing senescence.
Conclusions:
- CHD5 functions as a tumor suppressor gene in HCC.
- Epigenetic silencing via promoter hypermethylation contributes to HCC pathogenesis.
- Restoring CHD5 expression presents a potential therapeutic strategy for HCC.
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