Kruppel-Like Factor 6 (KLF6) Is a Tumor-Suppressor Gene Frequently Inactivated in Colorectal Cancer

Helen L. Reeves, Goutham Narla, Olagunju Ogunbiyi, Asif I. Haq, Amanda Katz, Sharon Benzeno, Eldad Hod, Noam Harpaz, Shlomit Goldberg, Sigal Tal-Kremer, Francis J. Eng, Michael J.P. Arthur, John A. Martignetti, Scott L. Friedman

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Background & Aims: Kruppel-like factor 6 (KLF6) is a ubiquitous zinc finger tumor suppressor that is often mutated in prostate cancer. Our aims were to establish the frequency of KLF6 inactivation in sporadic and inflammatory bowel disease (IBD)-associated colorectal cancers (CRC); to correlate these abnormalities with mutation and/or loss of TP53, APC, and K-RAS; and to characterize the behavior of mutant KLF6 in colon-derived cell lines. Methods: We analyzed DNA isolated from 50 microdissected CRC cases, including 35 sporadic and 15 IBD-associated tumors. Microsatellite analysis and direct sequencing were used to establish the incidence of microsatellite instability, KLF6 and TP53 allelic imbalance, and KLF6, K-RAS, TP53, and APC mutation. Loss of growth suppressive function of the CRC-derived KLF6 mutants was characterized by in vitro thymidine incorporation assays and Western blotting. Results: KLF6 was inactivated by loss and/or mutation in most sporadic and IBD-related CRCs. The KLF6 locus was deleted in at least 55% of tumors, and mutations were identified in 44%. Rates of KLF6 loss and mutation were similar to those of TP53 and K-RAS in the same samples. KLF6 mutations were present in tumors with either microsatellite or chromosomal instability and were more common, particularly in the IBD-related cancers, in the presence of wild-type APC. Unlike wild-type KLF6, cancer-derived KLF6 mutants neither suppressed growth nor induced p21 following transfection into cultured cells. Conclusions: Deregulation of KLF6 by a combination of allelic imbalance and mutation may play a role in the development of CRC.

Original languageEnglish (US)
Pages (from-to)1090-1103
Number of pages14
JournalGastroenterology
Volume126
Issue number4
DOIs
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Reeves, H. L., Narla, G., Ogunbiyi, O., Haq, A. I., Katz, A., Benzeno, S., Hod, E., Harpaz, N., Goldberg, S., Tal-Kremer, S., Eng, F. J., Arthur, M. J. P., Martignetti, J. A., & Friedman, S. L. (2004). Kruppel-Like Factor 6 (KLF6) Is a Tumor-Suppressor Gene Frequently Inactivated in Colorectal Cancer. Gastroenterology, 126(4), 1090-1103. https://doi.org/10.1053/j.gastro.2004.01.005