Disease relevance of KLF6

• Here, we show that the KLF6 gene is mutated in a subset of human prostate cancer [1].
• Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer [2].
• Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate and colon cancers, as well as in astrocytic gliomas [3].
• Here, we establish that KLF6 mediates growth inhibition through an interaction with cyclin D1, leading to reduced phosphorylation of the retinoblastoma protein (Rb) at Ser(795) [3].
• The binding of KLF6 to the iNOS promoter was significantly increased in Jurkat cells, primary T lymphocytes, and COS-7 cells subjected to NaCN-induced hypoxia, heat shock, serum starvation, and phorbol 12-myristate 13-acetate/ ionophore stimulation [4].

High impact information on KLF6

• Using a genetic screen in yeast, we have isolated B cell-derived cDNAs encoding Oct-binding factor 1 (OBF-1), a novel protein that specifically associates with Oct-1 and Oct-2 [5].
• A detailed antigenic phenotyping of neoplastic lymphoid cells showed that one patient had the immunophenotype T11+, Leu-1+, Leu-3+, Leu-2+, B1-, B2-, SIg-, LN1-, LN2-, the predominant phenotype for peripheral T-cell lymphoma; the others had T11-, Leu-1-, Leu-3-, Leu-2-, B1+, B2+, SIg+, LN1+, LN2+, consistent with a B-cell-derived lymphoma [6].
• Specific chromosomal translocations and the genesis of B-cell-derived tumors in mice and men [7].
• Two B-cell-derived tumours, human Burkitt's lymphoma (BL) and murine plasmacytoma (MPC), are regularly associated with a distinctive form of chromosomal translocation (for reviews see refs 1, 2) [8].
• KLF6, a candidate tumor suppressor gene mutated in prostate cancer [1].

Chemical compound and disease context of KLF6

• A single lysine-to-arginine point mutation (K209R) derived from prostate cancer reduces acetylation of KLF6 and abrogates its capacity to up-regulate endogenous p21(WAF1/cip1) and reduce cell proliferation [9].
• AIM: To investigate whether kruppel-like factor 6 (KLF6) plays an important role in the development and/or progression of colorectal cancer.METHODS: A total of 123 formalin-fixed and paraffin-embedded colorectal cancer specimens were analyzed by immunohistochemistry using tissue microarray for the expression of KLF6 protein [10].

Biological context of KLF6

• Kruppel-like factor 6 (KLF6) is a zinc finger transcription factor of unknown function [1].
• Loss-of-heterozygosity analysis revealed that one KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors [1].
• Unlike wild-type KLF6, cancer-derived KLF6 mutants neither suppressed growth nor induced p21 following transfection into cultured cells [2].
• CONCLUSIONS: Deregulation of KLF6 by a combination of allelic imbalance and mutation may play a role in the development of CRC [2].
• 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 [2].

Anatomical context of KLF6

• Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression [11].
• Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis [11].
• To examine the potential regulation of IGF-IR gene expression by KLF6, we measured KLF6 levels in prostate-derived cell lines displaying different levels of IGF-IR [12].
• Additionally, Zf9 localizes to the esophageal squamous epithelium by immunohistochemistry [13].
• In this study, we report that the expression of KLF6 is attenuated in human GBM when compared with primary astrocytes [14].

Associations of KLF6 with chemical compounds

• Loss of growth suppressive function of the CRC-derived KLF6 mutants was characterized by in vitro thymidine incorporation assays and Western blotting [2].
• Direct lysine acetylation of KLF6 peptides can be shown by mass spectrometry [9].
• Our data suggest a minor role of KLF6 mutation in colorectal carcinogenesis and underline the fact that the validity of sequence informations obtained from DNA extracted from formalin-fixed tissues may be limited [15].
• We also show that all KLF6 effects on c-Jun were largely dependent on phorbol ester (TPA/ionomycin) extracellular stimulation, which enhanced KLF6 nuclear translocation and transcriptional activity and modified its phosphorylation status [16].
• Treatment of two cell lines expressing KLF6 at low levels with 5-azacytidine did not induce KLF6 expression, suggesting that KLF6 down-regulation is not due to promoter hypermethylation [17].

Physical interactions of KLF6

• It was previously demonstrated that Krüppel-like factor 6 (KLF6) and specific-protein 1 (Sp1) bind to conserved sequence within the PSG-5 gene promoter [18].
• Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration [19].

Regulatory relationships of KLF6

• Mutation of both these sites abrogated the KLF6-induced enhancement of the 0.63-kb iNOS promoter activity [4].
• KLF6 exhibited an enhanced activity in p53-containing, compared with p53-null, cells [12].
• No difference was found in TGF-beta1 levels or TRAP-induced up regulation of PAC-1 [20].
• Bispecific CD3xCD19 antibodies and CD28 co-stimulating antibodies were used to activate T cells in bone marrow aspirates (n = 8) of children with B cell-derived acute lymphoblastic leukemia [21].
• Treatment of transduced megakaryocytes with a combination of agonists including epinephrine and the thrombin receptor-activating peptide induced the alphaIIbbeta(3) complex to form an activated conformation capable of binding fibrinogen as measured by PAC-1 antibody binding [22].

Other interactions of KLF6

• Rates of KLF6 loss and mutation were similar to those of TP53 and K-RAS in the same samples [2].
• MXI1, DMBT1, and KLF6 were excluded as important tumor-suppressor genes [23].
• Furthermore, we demonstrate that there is a physical interaction between GKLF and Zf9, a novel finding for Krüppel-like family members [13].
• The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact [13].
• Here we report the identification of Luna, the Drosophila progenitor of the mammalian KLF6/KLF7 group [24].

Analytical, diagnostic and therapeutic context of KLF6

• Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors [1].
• Within the 0.63-kb region, we identified two CACCC sites (-164 to -168 and -261 to -265) that bound KLF6 in both electrophoretic mobility shift and chromatin immunoprecipitation assays [4].
• Expression levels of KLF6 were significantly lost in 4 of 20 (20%) xenografts/cell lines of prostate cancer, as detected by RT-PCR and Northern blot analysis [25].
• To clarify the role of KLF6 in prostate cancers, particularly those that are high grade, we examined KLF6 for deletion, mutation, and loss of expression in 96 prostate cancer samples including 21 xenografts/cell lines [25].
• METHODS: Semiquantitative RT-PCR, Western blot analysis, immunofluorescence and in situ hybridization were used to investigate the expression of KLF6 mRNA and protein in normal and keratoconus corneas [26].

References