title: Regulation of AURKC expression by CpG island methylation in human cancer cells.
abstract: AURKC, a member of the Aurora kinase gene family, is highly expressed in testis but is either moderately expressed or repressed in most somatic cells. Varying expression of AURKC has been observed in human cancers, but the underlying mechanisms of differential expression have been investigated only to a limited extent. We investigated the role of promoter CpG methylation in the regulation of AURKC gene expression in human cancer cells, in relation to a recently reported AURKC transcription repressor PLZF/ZBTB16, implicated in transformation and tumorigenesis. AURKC and PLZF/ZBTB16 expression profiles were investigated in reference to CpG methylation status on the AURKC promoter experimentally, and also in The Cancer Genome Atlas (TCGA) dataset involving multiple cancer types. AURKC promoter showed dense to moderate hypermethylation correlating with low to moderate expression of the gene in normal somatic cells and cancer cell lines, while testis with high expression revealed marked hypo-methylation. Treatment with the demethylating agent, 5-aza-dC, but not the histone deacetylase (HDAC) inhibitor, TSA, led to elevated expression in cancer cell lines, indicating that promoter DNA methylation negatively regulates AURKC expression. High expression of PLZF in PLZF-transfected cells treated with 5-aza-dC only partially repressed expression of AURKC despite 5-aza-dC also inducing elevated PLZF expression. Analyses of the TCGA data showed differential expression of AURKC in multiple cancer types and stronger correlation of AURKC expression with CpG methylation compared to PLZF levels. These findings demonstrate that differential promoter CpG methylation is an important mechanism regulating AURKC expression in cancer cells.
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center at Kashiwa, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.|Molecular Genetic Technology Program, School of Health Professions, UT MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Vibhuti
authors.initials: V
authors.lastname: Srivastava
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.|Program in Human and Molecular Genetics, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
authors.forename: Apurva
authors.initials: A
authors.lastname: Hegde
authors.affiliation: Division of Epigenomics, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Department of Pediatrics, USDA Children's Nutrition Research Center-Baylor College of Medicine, 1100 Bates St., Ste. 8020, Houston, TX, 77030, USA.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Hematology and Clinical Rheumatology, Graduate School of Medical Sciences-Kumamoto University, Honjo 1-1-1, Kumamoto, 860-8556, Japan.
authors.forename: Koyu
authors.initials: K
authors.lastname: Hoshino
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Gonzalez
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics, Okayama University Medical School, Okayama, 700-8558, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasai
authors.affiliation: Center for Systems Biology, Department of Molecular and Cell Biology, University of Texas at Dallas, RL10, 800 W Campbell Road, Richardson, TX, 75080, USA.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Molecular Genetics, Okayama University Medical School, Okayama, 700-8558, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, UT MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Marcos R
authors.initials: MR
authors.lastname: Estecio
authors.affiliation: Division of Pathology and Laboratory Medicine, UT MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Hamilton
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, PAHB Room 154, 3307 N. Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.affiliation: Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Unit 2951, Life Science Plaza Building, 2130 W. Holcombe Blvd., Houston, TX, 77030, USA. ssen@mdanderson.org.
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
mesh_terms: D064108:Aurora Kinase C / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013737:Testis / Q000378:metabolism*
chemical_list: C576927:AURKC protein, human; D064108:Aurora Kinase C
keywords: Aurora kinase-C; Cell lines; Colon adenocarcinoma; CpG methylation; Epigenetic; PLZF