A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk

Goutham Narla, Analisa DiFeo, Helen L. Reeves, Daniel J. Schaid, Jennifer Hirshfeld, Eldad Hod, Amanda Katz, William B. Isaacs, Scott Hebbring, Akira Komiya, Shannon K. McDonnell, Kathleen E. Wiley, Steven J. Jacobsen, Sarah D. Isaacs, Patrick C. Walsh, S. Lilly Zheng, Bao Li Chang, Danielle M. Friedrichsen, Janet L. Stanford, Elaine A. OstranderArul M. Chinnaiyan, Mark A. Rubin, Jianfeng Xu, Stephen N. Thibodeau, Scott L. Friedman, John A. Martignetti

Research output: Contribution to journalArticle

175 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1213-1222
Number of pages10
JournalCancer research
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Narla, G., DiFeo, A., Reeves, H. L., Schaid, D. J., Hirshfeld, J., Hod, E., Katz, A., Isaacs, W. B., Hebbring, S., Komiya, A., McDonnell, S. K., Wiley, K. E., Jacobsen, S. J., Isaacs, S. D., Walsh, P. C., Zheng, S. L., Chang, B. L., Friedrichsen, D. M., Stanford, J. L., ... Martignetti, J. A. (2005). A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer research, 65(4), 1213-1222. https://doi.org/10.1158/0008-5472.CAN-04-4249