Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer.
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.
Reeves
Helen L
HL
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
Narla
Goutham
G
Ogunbiyi
Olagunju
O
Haq
Asif I
AI
Katz
Amanda
A
Benzeno
Sharon
S
Hod
Eldad
E
Harpaz
Noam
N
Goldberg
Shlomit
S
Tal-Kremer
Sigal
S
Eng
Francis J
FJ
Arthur
Michael J P
MJ
Martignetti
John A
JA
Friedman
Scott L
SL
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*
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators