title: Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer.
abstract: BACKGROUND
  MTO1 and MRPL41 are nuclear-encoded mitochondrial genes encoding a mitochondrial tRNA-modifying enzyme and a mitochondrial ribosomal protein, respectively. Although both genes have been known to have potential roles in cancer, little is known about their molecular regulatory mechanism, particularly from an epigenetic approach. In this study, we aimed to address their epigenetic regulation through the estrogen receptor (ER) in breast cancer.
  
  
  METHODS
  Digital differential display (DDD) was conducted to identify mammary gland-specific gene candidates including MTO1 and MRPL41. Promoter CpG methylation and expression in breast cancer cell lines and tissues were examined by methylation-specific PCR and real time RT-PCR. Effect of estradiol (E2), tamoxifen, and trichostatin A (TSA) on gene expression was examined in ER + and ER- breast cancer cell lines. Chromatin immunoprecipitation and luciferase reporter assay were performed to identify binding and influencing of the ER to the promoters.
  
  
  RESULTS
  Examination of both cancer tissues and cell lines revealed that the two genes showed an opposite expression pattern according to ER status; higher expression of MTO1 and MRPL41 in ER- and ER+ cancer types, respectively, and their expression levels were inversely correlated with promoter methylation. Tamoxifen, E2, and TSA upregulated MTO1 expression only in ER+ cells with no significant changes in ER- cells. However, these chemicals upregulated MRPL41 expression only in ER- cells without significant changes in ER+ cells, except for tamoxifen that induced downregulation. Chromatin immunoprecipitation and luciferase reporter assay identified binding and influencing of the ER to the promoters and the binding profiles were differentially regulated in ER+ and ER- cells.
  
  
  CONCLUSIONS
  These results indicate that different epigenetic status including promoter methylation and different responses through the ER are involved in the differential expression of MTO1 and MRPL41 in breast cancer.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Byungtak
authors.initials: B
authors.lastname: Kim
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Seongeun
authors.initials: S
authors.lastname: Kang
authors.forename: Sung-Bin
authors.initials: SB
authors.lastname: Park
authors.forename: Gookjoo
authors.initials: G
authors.lastname: Jeong
authors.affiliation: Department of Life Science, Dongguk University-Seoul, Seoul 100-715, Korea. rorerr@ncc.re.kr.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kang
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D024101:Mitochondrial Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements; D012269:Ribosomal Proteins / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D006877:Hydroxamic Acids; C502654:MRPL41 protein, human; C492006:MTO1 protein, human; D024101:Mitochondrial Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D012269:Ribosomal Proteins; D013629:Tamoxifen; C012589:trichostatin A; D004958:Estradiol