title: Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.forename: Olagunju
authors.initials: O
authors.lastname: Ogunbiyi
authors.forename: Asif I
authors.initials: AI
authors.lastname: Haq
authors.forename: Amanda
authors.initials: A
authors.lastname: Katz
authors.forename: Sharon
authors.initials: S
authors.lastname: Benzeno
authors.forename: Eldad
authors.initials: E
authors.lastname: Hod
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: Shlomit
authors.initials: S
authors.lastname: Goldberg
authors.forename: Sigal
authors.initials: S
authors.lastname: Tal-Kremer
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Eng
authors.forename: Michael J P
authors.initials: MJ
authors.lastname: Arthur
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D017354:Point Mutation; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators