title: Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells.
abstract: DNA hypermethylation is a key epigenetic mechanism for the silencing of many genes in cancer. Hinokitiol, a tropolone-related natural compound, is known to induce apoptosis and cell cycle arrest and has anti-inflammatory and anti-tumor activities. However, the relationship between hinokitiol and DNA methylation is not clear. The aim of our study was to explore whether hinokitiol has an inhibitory ability on the DNA methylation in colon cancer cells.
  
  
  
  MTT data showed that hinokitiol had higher sensitivity in colon cancer cells, HCT-116 and SW480, than in normal colon cells, CCD18Co. Hinokitiol reduced DNA methyltransferase 1 (DNMT1) and ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression in HCT-116 cells. In addition, the expression of ten-eleven translocation protein 1 (TET1), a known DNA demethylation initiator, was increased by hinokitiol treatment. ELISA and FACS data showed that hinokitiol increased the 5-hydroxymethylcytosine (5hmC) level in the both colon cancer cells, but 5-methylcytosine (5mC) level was not changed. Furthermore, hinokitiol significantly restored mRNA expression of O6-methylguanine DNA methyltransferase (MGMT), carbohydrate sulfotransferase 10 (CHST10), and B-cell translocation gene 4 (BTG4) concomitant with reduction of methylation status in HCT-116 cells.
  
  
  
  These results indicate that hinokitiol may exert DNA demethylation by inhibiting the expression of DNMT1 and UHRF1 in colon cancer cells.
authors.affiliation: Department of Anatomy, Institute of Human Genetics, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Jung Seon
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Department of Anatomy, Institute of Human Genetics, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Young Ha
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Pathology, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Ji Wook
authors.initials: JW
authors.lastname: Moon
authors.affiliation: Department of Anatomy, Institute of Human Genetics, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Institute of Human Genetics, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea. parksh@korea.ac.kr.
authors.forename: Sun-Hwa
authors.initials: SH
authors.lastname: Park
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism; D039821:Monoterpenes / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D039821:Monoterpenes; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D014334:Tropolone; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; C009479:beta-thujaplicin
keywords: Anti-tumor activities; Colonic neoplasm; DNA methylation; DNA methylation inhibitor; Hinokitiol