title: An enhancer from the 8q24 prostate cancer risk region is sufficient to direct reporter gene expression to a subset of prostate stem-like epithelial cells in transgenic mice.
abstract: Regions in the 8q24 gene desert contribute significantly to the risk of prostate cancer and other adult cancers. This region contains several DNA regions with enhancer activity in cultured cells. One such segment, histone acetylation peak 10 (AcP10), contains a risk single nucleotide polymorphism (SNP) that is significantly associated with the pathogenesis of colorectal, prostate and other cancers. The mechanism by which AcP10 influences cancer risk remains unknown. Here we show that AcP10 contains a sequence that is highly conserved across terrestrial vertebrates and is capable in transgenic mice of directing reporter gene expression to a subset of prostate lumenal epithelial cells. These cells include a small population of Nkx3.1-positive cells that persist even after androgen ablation. Castration-resistant Nkx3.1-positive (CARN) cells were shown by others to function both as stem cells and cells of origin of prostate cancer. Our results thus provide a mechanism by which AcP10 could influence prostate cancer risk.
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Cancer Center, USC Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
authors.forename: Man-Chun
authors.initials: MC
authors.lastname: Ting
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liao
authors.forename: Chunli
authors.initials: C
authors.lastname: Yan
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
authors.forename: Pradip
authors.initials: P
authors.lastname: Roy-Burman
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.forename: Robert
authors.initials: R
authors.lastname: Maxson
mesh_terms: D000818:Animals; D001483:Base Sequence; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D004742:Enhancer Elements, Genetic; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D017930:Genes, Reporter / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000235:genetics*; D012307:Risk Factors; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014714:Vertebrates / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D001616:beta-Galactosidase