title: ENSA expression correlates with attenuated tumor propagation in liver cancer.
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.
authors.affiliation: Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Kuo
authors.forename: Ping-Yi
authors.initials: PY
authors.lastname: Lin
authors.forename: Wan-Ling
authors.initials: WL
authors.lastname: Chuang
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Hsu
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.forename: Chia-Huei
authors.initials: CH
authors.lastname: Lee
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Leu
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Hsiao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D010455:Peptides; C075663:endosulfine; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases
keywords: 5-Aza; 5-aza-2′-deoxycytidine; Chromatin immunoprecipitation; DNA methylation; ENSA; Epigenetic; H3K27me3; Liver cancer; MSC; endosulfine alpha; histone 3 lysine 27 trimethylation; mesenchymal stem cell