title: A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.
abstract: Prostate cancer is a leading and increasingly prevalent cause of cancer death in men. Whereas family history of disease is one of the strongest prostate cancer risk factors and suggests a hereditary component, the predisposing genetic factors remain unknown. We first showed that KLF6 is a tumor suppressor somatically inactivated in prostate cancer and since then, its functional loss has been further established in prostate cancer cell lines and other human cancers. Wild-type KLF6, but not patient-derived mutants, suppresses cell growth through p53-independent transactivation of p21. Here we show that a germline KLF6 single nucleotide polymorphism, confirmed in a tri-institutional study of 3,411 men, is significantly associated with an increased relative risk of prostate cancer in men, regardless of family history of disease. This prostate cancer-associated allele generates a novel functional SRp40 DNA binding site and increases transcription of three alternatively spliced KLF6 isoforms. The KLF6 variant proteins KLF6-SV1 and KLF6-SV2 are mislocalized to the cytoplasm, antagonize wtKLF6 function, leading to decreased p21 expression and increased cell growth, and are up-regulated in tumor versus normal prostatic tissue. Thus, these results are the first to identify a novel mechanism of self-encoded tumor suppressor gene inactivation and link a relatively common single nucleotide polymorphism to both regulation of alternative splicing and an increased risk in a major human cancer.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.forename: Analisa
authors.initials: A
authors.lastname: Difeo
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hirshfeld
authors.forename: Eldad
authors.initials: E
authors.lastname: Hod
authors.forename: Amanda
authors.initials: A
authors.lastname: Katz
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Scott
authors.initials: S
authors.lastname: Hebbring
authors.forename: Akira
authors.initials: A
authors.lastname: Komiya
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Wiley
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jacobsen
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Walsh
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Bao-Li
authors.initials: BL
authors.lastname: Chang
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Friedrichsen
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D048708:Cell Growth Processes / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D000068103:Serine-Arginine Splicing Factors