title: Transcription Factor KLF5 Binds a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk.
abstract: It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single-nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of the genome. Here, it is demonstrated that bladder cancer cells heterozygous for this SNP exhibit biased allelic expression of CCNE1 with 1.5-fold more transcription occurring from the risk allele. Furthermore, using chromatin immunoprecipitation assays, a novel enhancer element was identified within the first intron of CCNE1 that binds Kruppel-like Factor 5 (KLF5), a known transcriptional activator in bladder cancer. Moreover, the data reveal that the presence of rs200996365, a SNP in high-linkage disequilibrium with rs8102137 residing in the center of a KLF5 motif, alters KLF5 binding to this genomic region. Through luciferase assays and CRISPR-Cas9 genome editing, a novel polymorphic intronic regulatory element controlling CCNE1 transcription is characterized. These studies uncover how a cancer-associated polymorphism mechanistically contributes to an increased predisposition for bladder cancer development.
  
  
  
  A polymorphic KLF5 binding site near the CCNE1 gene explains genetic risk identified through GWAS. Mol Cancer Res; 14(11); 1078-86. ©2016 AACR.
authors: Department of Genetics, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors: Jillian M
authors: JM
authors: Pattison
authors: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors: Valeriya
authors: V
authors: Posternak
authors: Department of Genetics, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire. mcole@dartmouth.edu.|Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire.
authors: Michael D
authors: MD
authors: Cole
mesh_terms: D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas