title: An epigenetic screen unmasks metallothioneins as putative contributors to renal cell carcinogenesis.
abstract: OBJECTIVE
  Functional epigenetic studies aimed to re-express transcriptionally silenced genes in renal cell carcinoma (RCC) may facilitate the ongoing search for appropriate markers supporting clinical decision-making.
  
  
  METHODS
  The RCC cell line A-498 was treated with the DNA methyltransferase inhibitor zebularine under low-cytotoxicity conditions. RNA chip analyses revealed several upregulated transcripts that were further validated by qPCR on 49 matched pairs of human kidney tissues to identify suitable marker candidates.
  
  
  RESULTS
  Members of the metallothionein (MT) group were remarkably downregulated in tumor tissues. MT1G and MT1H expression was decreased in 98% of cases, whereas MT2A expression was downregulated in 73% of all cases. Comparison of 308 reactivated transcripts upregulated more than 1.5-fold to published data revealed a high number of shared candidates, which supports the consistency of this experimental approach.
  
  
  CONCLUSIONS
  MTs were found to be transcriptionally inactivated in human RCC. Our observations support the hypothesis of a possible involvement of these metalloproteins in renal cell carcinogenesis. Additional functional studies of these genes may provide clues for understanding renal cancers as essentially metabolic diseases.
authors.affiliation: Klinik für Urologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Imad
authors.initials: I
authors.lastname: Alkamal
authors.forename: Odiljon
authors.initials: O
authors.lastname: Ikromov
authors.forename: Angelika
authors.initials: A
authors.lastname: Tölle
authors.forename: Tom Florian
authors.initials: TF
authors.lastname: Fuller
authors.forename: Ahmed
authors.initials: A
authors.lastname: Magheli
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Hans
authors.initials: H
authors.lastname: Krause
authors.forename: Carsten
authors.initials: C
authors.lastname: Kempkensteffen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C499629:MT1G protein, human; C491053:MT2A protein, human; D012333:RNA, Messenger; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D008668:Metallothionein; D015254:DNA Modification Methylases