title: Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma.
abstract: Metastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrent chromosomal aberrations, suggesting the location of either tumor suppressor genes or oncogenes. Transcription factor 21 (TCF21) belongs to the class A of the basic helix-loop-helix family with reported functions in early lung and kidney development as well as tumor suppressor function in the malignancies of the lung and head and neck. In this study, we combined quantitative DNA methylation analysis in patient biopsies and in their derived cell lines to demonstrate that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation and TCF21 promoter DNA methylation is correlated with decreased survival in metastatic skin melanoma patients. In addition, the chromosomal location of TCF21 on 6q23-q24 coincides with the location of a postulated metastasis suppressor in melanoma. Functionally, TCF21 binds the promoter of the melanoma metastasis-suppressing gene, KiSS1, and enhances its gene expression through interaction with E12, a TCF3 isoform and with TCF12. Loss of TCF21 expression results in loss of KISS1 expression through loss of direct interaction of TCF21 at the KISS1 promoter. Finally, overexpression of TCF21 inhibits motility of C8161 melanoma cells. These data suggest that epigenetic downregulation of TCF21 is functionally involved in melanoma progression and that it may serve as a biomarker for aggressive tumor behavior.
authors.affiliation: German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Khelifa
authors.initials: K
authors.lastname: Arab
authors.forename: Laura T
authors.initials: LT
authors.lastname: Smith
authors.forename: Andreas
authors.initials: A
authors.lastname: Gast
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Joseph Po-Hsien
authors.initials: JP
authors.lastname: Huang
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Allan V
authors.initials: AV
authors.lastname: Espinosa
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Carl D
authors.initials: CD
authors.lastname: Morrison
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D002465:Cell Movement; D002648:Child; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D059648:Kisspeptins; D008156:Luciferases; D012333:RNA, Messenger; C106628:KISS1 protein, human; C491825:TCF21 protein, human