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Updated: Sep 23, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis
Miriam Recalde1, María Gárate-Rascón1, José María Herranz1,2
1Program of Hepatology, Centre of Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
Background:
Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis.
Methods And Results:
The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis.
Conclusions:
Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.
Insights
Downregulation of specific long noncoding RNAs (lncRNAs) via DNA methylation impairs liver cell differentiation and worsens prognosis in hepatocellular carcinoma (HCC) patients.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their roles in cancer development.
- Hepatocellular carcinoma (HCC) is a major global health concern where lncRNAs are implicated.
Purpose of the Study:
- To elucidate the mechanism of lncRNA inhibition in HCC.
- To determine the contribution of specific lncRNAs to hepatocarcinogenesis.
Main Methods:
- Validation of 35 downregulated lncRNAs (Top35 LNDH) in HCC patient cohorts and cell lines.
- Analysis of promoter methylation status and effect of demethylating agents.
- Assessment of lncRNA expression in different tissues and cell differentiation states.
- Investigation of lncRNA knockdown effects on hepatic gene expression.
- Correlation analysis with tumor differentiation grade and patient survival.
Main Results:
- Top35 LNDH are significantly downregulated in HCC, associated with promoter hypermethylation.
- Demethylation treatment restored Top35 LNDH expression in HCC cell lines.
- Top35 LNDH are preferentially expressed in adult healthy liver and induced during differentiation.
- Knockdown of Top35 LNDH affected expression of other liver-specific genes.
- Top35 LNDH expression positively correlates with tumor differentiation and better patient prognosis.
Conclusions:
- The identified Top35 LNDH are crucial for establishing the hepatic differentiation signature.
- DNA methylation-mediated downregulation of Top35 LNDH during hepatocarcinogenesis compromises differentiation and patient outcomes.
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