TY - JOUR
T1 - A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk
AU - Narla, Goutham
AU - DiFeo, Analisa
AU - Reeves, Helen L.
AU - Schaid, Daniel J.
AU - Hirshfeld, Jennifer
AU - Hod, Eldad
AU - Katz, Amanda
AU - Isaacs, William B.
AU - Hebbring, Scott
AU - Komiya, Akira
AU - McDonnell, Shannon K.
AU - Wiley, Kathleen E.
AU - Jacobsen, Steven J.
AU - Isaacs, Sarah D.
AU - Walsh, Patrick C.
AU - Zheng, S. Lilly
AU - Chang, Bao Li
AU - Friedrichsen, Danielle M.
AU - Stanford, Janet L.
AU - Ostrander, Elaine A.
AU - Chinnaiyan, Arul M.
AU - Rubin, Mark A.
AU - Xu, Jianfeng
AU - Thibodeau, Stephen N.
AU - Friedman, Scott L.
AU - Martignetti, John A.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - 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 snppressor 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.
AB - 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 snppressor 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.
UR - http://www.scopus.com/inward/record.url?scp=13944252065&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13944252065&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-04-4249
DO - 10.1158/0008-5472.CAN-04-4249
M3 - Article
C2 - 15735005
AN - SCOPUS:13944252065
SN - 0008-5472
VL - 65
SP - 1213
EP - 1222
JO - Cancer research
JF - Cancer research
IS - 4
ER -