688

KLF5

BTEB2|CKLF|IKLF;Kruppel-like factor 5 (intestinal);KLF5;Kruppel-like factor 5 (intestinal)

BTE-binding protein 2|GC box binding protein 2|GC-box-binding protein 2|Krueppel-like factor 5|basic transcription element binding protein 2|basic transcription element-binding protein 2|colon krueppel-like factor|colon kruppel-like factor|intestinal-enri

13q22.1

protein-coding

Count: 2; Pubmed_search,Generif

BACKGROUND: Previous studies mapped a region at the q21 band of chromosome 13 (13q21), which is frequently deleted in various human cancers including prostate cancer, suggesting the existence of a tumor suppressor gene at 13q21. The target gene of deletion in prostate cancer, however, has not been identified at present. METHODS: We examined four non-neoplastic and 18 neoplastic prostatic cell lines or xenografts. Homozygous/hemizygous deletion was detected by assays of duplex PCR and real-time PCR. expression levels of genes were determined by the methods of RT-PCR, real time PCR, and northern blot analysis. mutations of KLF5 were detected by the approaches of single strand conformational polymorphism (SSCP) and direct sequencing. For the detection of promoter methylation, Southern blotting of genomic DNA and restriction digestion or SSCP analysis of methylation specific PCR products were used. Finally, an expression plasmid of KLF5 was introduced into prostate cancer cell lines with reduced KLF5 expression to investigate colony formation for cell growth. RESULTS: A 2-Mb region of homozygous deletion at 13q21 was detected in the LUCaP70 xenograft of prostate cancer. This region of deletion was further narrowed to 142 Kb by a hemizygous deletion in the NCI-H660 cell line. KLF5 was identified as the only complete gene in the smallest region of deletion. Quantitative deletion of KLF5 genome occurred in six of the 18 (33%) prostate cancer xenografts/cell lines. Each of the six samples with deletion also showed loss of expression for KLF5, suggesting that hemizygous deletion is one mechanism for loss of KLF5 expression. In total, 16 of the 18 cases (89%) showed loss of KLF5 expression at different degrees. In contrast, mutations and promoter methylations were not detected in any of the samples. Functionally, restoration of KLF5 in DU 145 and 22Rv1 cell lines significantly inhibited their growth in vitro. CONCLUSIONS: Frequent genomic deletion and loss of expression as well as cell growth suppression indicate that KLF5 is a reasonable candidate for the tumor suppressor gene at 13q21 in prostate cancer. mutation and promoter methylation are not common mechanisms for the inactivation of KLF5 in prostate cancer.CI - Copyright 2003 Wiley-Liss, Inc.

The 13q21 tumor suppressor locus, as defined by chromosomal deletion, harbors the KLF5 transcription factor which may have tumor suppressor function. To investigate whether KLF5 plays a role in breast cancer, we evaluated all genes and/or expressed sequence tags (ESTs) within a 3.3 Mb common region of deletion at 13q21. Of these, only KLF5 mRNA was expressed at high levels in non-neoplastic breast epithelial cells and in normal human mammary tissue, but at lower levels in various breast cancer cell lines. Using the real time TaqMan PCR assay, hemizygous deletion at KLF5 was detected in 13 out of 30, or 43% of breast cancer cell lines tested, and various degrees of loss of expression were detected in 21 out of 30, or 70% of these cell lines. Each of the cases with hemizygous deletion also exhibited loss of KLF5 expression, suggesting that loss of expression can result from chromosomal deletion, and that KLF5 may undergo haploinsufficiency during carcinogenesis. Only one of the 30 breast cancer cell lines tested exhibited a mutation in KLF5, and neither promoter methylation nor homozygous deletion was detected in any of the cell lines. In contrast, loss of heterozygosity (LOH) was frequently detected at KLF5. Re-expression of wild-type KLF5 in T-47D breast cancer cells significantly inhibited colony formation in these cells. Of the KLF5-transfected clones that did form colonies, none were found to express KLF5 mRNA. These findings suggest that loss of function by deletion and/or loss of expression frequently occurs at KLF5, and KLF5 suppresses tumor cell growth in breast cancer.