Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer☆

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

doi:10.1053/j.gastro.2004.01.005

Cited by 162 publications

(188 citation statements)

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“…In contrast with the other studies, they only analyzed exon 2. None of the other studies included methods to [10][11][12][13] (ranging between 0 and 15%) and colorectal carcinoma [14][15][16][17][18] (ranging between 0 and 44%). Similar to prostate cancer, the first studies conducted on these other tumors indicated a high frequency of mutation, but this was not reproduced in subsequent reports.…”

Section: Discussionmentioning

confidence: 99%

“…9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%.…”

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confidence: 99%

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KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

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Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

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“…Fluorescent loss of heterozygosity (LOH) analysis using genomic DNA from paired control/tumor tissue was performed as described previously. 7,9 KLF6 is located 4.1 Mb from the telomeric end of chromosome 10p and is flanked by microsatellite markers D10S594 and D10S591, located 1.7 and 4.8 Mb, respectively, from the telomere ( Table 1). The KLF6-specific markers KLF6M1, M2, and M4 flank the KLF6 locus by 40 kb centromerically and 10 kb and 20 kb telomerically, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…KLF6 exon 2 polymerase chain reaction products from normal and tumor-derived genomic DNA were generated using combinations of nine forward and reverse primers that generated overlapping amplicons as described previously. 9 All mutations were confirmed via bidirectional sequencing in 2 independent polymerase chain reaction reactions, and, for the T179I mutation, further confirmed via restriction digest as described previously. 9 Cell Culture and Transient Transfection.…”

Section: Methodsmentioning

confidence: 99%

“…Krüppel-like factor 6 (KLF6), a ubiquitously expressed zinc finger transcription factor, 6 has been identified as a tumor suppressor gene in prostate, 7,8 colon, 9 and nasopharyngeal 10 cancers, as well as astrocytic gliomas. 11 Moreover, downregulation of KLF6 messenger RNA levels has been described in lung 12,13 and esophageal 14 cancers, the latter also being associated with promoter methylation.…”

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Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

et al. 2004

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Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Krüppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39% of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild-type KLF6 decreased cellular proliferation of HepG2 cells, while patient-derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors.

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Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta

et al. 2022

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Trophoblast cell differentiation is of paramount importance for successful pregnancy. Krüppel‐like factor 6 (KLF6), a transcription factor with diverse roles in cell physiology and tumor biology, is required for trophoblast differentiation through the syncytial pathway. Herein, we demonstrate that extravillous trophoblast (EVT) cell migration and mesenchymal phenotype are increased upon KLF6 downregulation or the expression of a deletion mutant lacking its transcriptional regulatory domain (KΔac). Raman spectroscopy revealed molecular modifications compatible with increased differentiation in cells stably expressing the KΔac mutant. Moreover, abnormally invasive placenta showed lower KLF6 immunostaining compared with the normal placenta. Thus, impaired KLF6 expression or function stimulates EVT migration and differentiation in vitro and may contribute to the physiopathology of the abnormally invasive placenta.

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Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer☆

Cited by 162 publications

References 39 publications

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta

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