title: 4C-seq revealed long-range interactions of a functional enhancer at the 8q24 prostate cancer risk locus.
abstract: Genome-wide association studies (GWAS) have identified >100 independent susceptibility loci for prostate cancer, including the hot spot at 8q24. However, how genetic variants at this locus confer disease risk hasn't been fully characterized. Using circularized chromosome conformation capture (4C) coupled with next-generation sequencing and an enhancer at 8q24 as "bait", we identified genome-wide partners interacting with this enhancer in cell lines LNCaP and C4-2B. These 4C-identified regions are distributed in open nuclear compartments, featuring active histone marks (H3K4me1, H3K4me2 and H3K27Ac). Transcription factors NKX3-1, FOXA1 and AR (androgen receptor) tend to occupy these 4C regions. We identified genes located at the interacting regions, and found them linked to positive regulation of mesenchymal cell proliferation in LNCaP and C4-2B, and several pathways (TGF beta signaling pathway in LNCaP and p53 pathway in C4-2B). Common genes (e.g. MYC and POU5F1B) were identified in both prostate cancer cell lines. However, each cell line also had exclusive genes (e.g. ELAC2 and PTEN in LNCaP and BRCA2 and ZFHX3 in C4-2B). In addition, BCL-2 identified in C4-2B might contribute to the progression of androgen-refractory prostate cancer. Overall, our work reveals key genes and pathways involved in prostate cancer onset and progression.
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA.|Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.|Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Cai
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sewoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA.|Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.|Department of Psychiatry, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.|Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Farnham
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.|Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Wange
authors.initials: W
authors.lastname: Lu
mesh_terms: D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D014157:Transcription Factors