A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk.
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.
Narla
Goutham
G
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Difeo
Analisa
A
Reeves
Helen L
HL
Schaid
Daniel J
DJ
Hirshfeld
Jennifer
J
Hod
Eldad
E
Katz
Amanda
A
Isaacs
William B
WB
Hebbring
Scott
S
Komiya
Akira
A
McDonnell
Shannon K
SK
Wiley
Kathleen E
KE
Jacobsen
Steven J
SJ
Isaacs
Sarah D
SD
Walsh
Patrick C
PC
Zheng
S Lilly
SL
Chang
Bao-Li
BL
Friedrichsen
Danielle M
DM
Stanford
Janet L
JL
Ostrander
Elaine A
EA
Chinnaiyan
Arul M
AM
Rubin
Mark A
MA
Xu
Jianfeng
J
Thibodeau
Stephen N
SN
Friedman
Scott L
SL
Martignetti
John A
JA
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
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