Epigenetic regulation of the tumor suppressor gene TCF21 on 6q23-q24 in lung and head and neck cancer.
The identification of tumor suppressor genes has classically depended on their localization within recurrent regions of loss of heterozygosity. According to Knudson's two-hit hypothesis, the remaining allele is lost, either genetically or, more recently identified, through epigenetic events. To date, retrospective analyses have determined promoter methylation as a common alternative alteration in cancer cells to silence cancer-related genes. Here we report an application of restriction landmark genomic scanning that allows for DNA methylation profiling along a region of recurrent loss of heterozygosity at chromosome 6q23-q24. This approach resulted in the identification of a tumor suppressor gene, TCF21, which is frequently lost in human malignancies. We demonstrate that TCF21 is expressed in normal lung airway epithelial cells and aberrantly methylated and silenced in the majority of head and neck squamous cell carcinomas and non-small-cell lung cancers analyzed. TCF21 is known to regulate mesenchymal cell transition into epithelial cells, a property that has been shown to be deficient in carcinomas. We further demonstrate that exogenous expression of TCF21 in cells that have silenced the endogenous TCF21 locus resulted in a reduction of tumor properties in vitro and in vivo.
Smith
Laura T
LT
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA.
Lin
Mauting
M
Brena
Romulo M
RM
Lang
James C
JC
Schuller
David E
DE
Otterson
Gregory A
GA
Morrison
Carl D
CD
Smiraglia
Dominic J
DJ
Plass
Christoph
C
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6 / Q000648:ultrastructure*; D019175:DNA Methylation; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016678:Genome; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D001374:Azacitidine; D051792:Basic Helix-Loop-Helix Proteins; D000077209:Decitabine; D008156:Luciferases; D013447:Sulfites; C491825:TCF21 protein, human