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ENSA expression correlates with attenuated tumor propagation in liver cancer
Yao-Li Chen1, Ming-Han Kuo, Ping-Yi Lin
1Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract:
Endosulfine alpha (ENSA) is an endogenous ligand of sulfonylurea receptor that was reported to be associated with an ATP-dependent potassium channel that controls insulin release and the onset of type 2 diabetes. ENSA also interacts with microtubule-associated serine/threonine-protein kinase-like (MASTL) to regulate the cell cycle. Previously, we identified ENSA as a possible bivalent gene in mesenchymal stem cells (MSCs) and hypothesized its methylation might determine cellular differentiation and transformation. Because there was no link between aberrant ENSA expression and tumorigenesis, we aimed to determine if ENSA is abnormally regulated in liver cancer and plays a role in liver cancer propagation. The epigenetic states of the ENSA promoter were evaluated in different cancer cell lines and patient samples. ENSA was overexpressed in a liver cancer cell line, and its interaction with MASTL and possible tumor suppression capabilities were also determined in cultured cells and mice. Distinct ENSA promoter methylation was observed in liver cancer (n=100 pairs) and breast cancer (n=100 pairs). ENSA was predominantly hypomethylated in liver cancer but was hypermethylated in breast cancer. Overexpressed ENSA interacts with MASTL and suppresses hepatic tumor growth. We also found that ENSA is hypermethylated in CD90-expressing (CD90(+)) cells compared to CD90 non-expressing (CD90(-)) liver cancer cells. These data reveal ENSA methylation changes during hepatic tumor evolution. Overexpressed ENSA suppresses tumor growth in an established hepatic cell line whereas hypermethylated ENSA might help maintain liver cancer initiating cells.
Insights
Endosulfine alpha (ENSA) methylation patterns differ in liver and breast cancers. Overexpressed ENSA suppresses liver tumor growth, while its hypermethylation may maintain liver cancer stem cells.
Area of Science:
- Molecular Biology
- Cancer Epigenetics
- Cell Biology
Background:
- Endosulfine alpha (ENSA) is an endogenous ligand for the sulfonylurea receptor, linked to insulin release and type 2 diabetes.
- ENSA also regulates the cell cycle through interaction with MASTL and was previously identified as a bivalent gene in mesenchymal stem cells.
Purpose of the Study:
- To investigate the role of ENSA in liver cancer, focusing on its epigenetic regulation and potential tumor suppressive functions.
- To determine if ENSA promoter methylation differs between liver and breast cancers and its implications in hepatic tumorigenesis.
Main Methods:
- Analysis of ENSA promoter methylation in liver and breast cancer cell lines and patient samples (n=100 pairs each).
- Evaluation of ENSA expression and its interaction with MASTL in liver cancer cell lines and in vivo mouse models.
- Assessment of ENSA methylation status in CD90-expressing versus CD90 non-expressing liver cancer cells.
Main Results:
- Distinct ENSA promoter methylation patterns were observed: hypomethylation in liver cancer and hypermethylation in breast cancer.
- Overexpressed ENSA demonstrated tumor suppressive capabilities in a hepatic cell line and in mice by interacting with MASTL.
- ENSA was found to be hypermethylated in CD90(+) liver cancer cells compared to CD90(-) cells, indicating methylation changes during tumor evolution.
Conclusions:
- ENSA methylation is altered during hepatic tumor progression, with hypomethylation associated with liver cancer development.
- Overexpression of ENSA exerts tumor suppressor effects in liver cancer, whereas its hypermethylation may contribute to maintaining cancer-initiating cells.
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