Kaiso Contributes to DNA Methylation-Dependent Silencing of Tumor Suppressor Genes in Colon Cancer Cell Lines

Lopes, Eloisi Caldas; Valls, Ester; Figueroa, María E.; Mazur, Alexander; Meng, Fan; Chiosis, Gabriela; Laird, Peter W.; Schreiber‐Agus, Nicole; Greally, John M.; Prokhortchouk, Egor; Melnick, Ari

doi:10.1158/0008-5472.can-08-0344

Cited by 108 publications

(115 citation statements)

References 29 publications

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“…The minor groove interactions, made by residues in the C-terminal extension following ZF3, are required for high-affinity binding to both KBS and methylated DNA (10). The present structural analysis reveals the mechanism of DNA recognition by the Kaiso zinc finger domain and represents a first step toward a molecular-level description of the complex pathways involved in methylation-dependent silencing of tumorsuppressor genes and in the regulation of the Wnt signaling pathway by Kaiso (14,32). Once bound to DNA, Kaiso represses the target gene by recruiting an N-CoR/histone deacetylase complex through its N-terminal BTB/POZ domain (33).…”

Section: Discussionmentioning

confidence: 81%

“…Kaiso binds to and silences aberrantly methylated tumor-suppressor and DNA-repair genes in cancer cells (14). Specific Kaiso-binding sites are found in the promoters of several target genes (matrilysin, cyclin-D1, siamois, c-myc, and Wnt11) regulated by the Wnt signaling pathway, which plays a critical role in early development and tumor progression (9, 15, 16).…”

mentioning

confidence: 99%

“…The interaction of Kaiso with p120 ctn has been implicated in regulation of canonical and noncanonical Wnt signaling pathways through a mechanism that involves KBS recognition (15, 16). Additionally, there is increasing evidence that Kaiso expression levels are elevated in tumorigenesis, indicating that Kaiso may play a direct role in modulating cancer through transcriptional control of aberrantly methylated and KBS-containing genes (14,19,20). It still is unclear whether the transcriptional regulation of the two distinctly different DNA sequences is synergistic in nature or mutually exclusive.…”

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confidence: 99%

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Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

Buck‐Koehntop

Stanfield

Ekiert

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

160

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Methylation of CpG dinucleotides in DNA is a common epigenetic modification in eukaryotes that plays a central role in maintenance of genome stability, gene silencing, genomic imprinting, development, and disease. Kaiso, a bifunctional Cys 2 His 2 zinc finger protein implicated in tumor-cell proliferation, binds to both methylated CpG (mCpG) sites and a specific nonmethylated DNA motif (TCCTGCNA) and represses transcription by recruiting chromatin remodeling corepression machinery to target genes. Here we report structures of the Kaiso zinc finger DNA-binding domain in complex with its nonmethylated, sequence-specific DNA target (KBS) and with a symmetrically methylated DNA sequence derived from the promoter region of E-cadherin. Recognition of specific bases in the major groove of the core KBS and mCpG sites is accomplished through both classical and methyl CH···O hydrogen-bonding interactions with residues in the first two zinc fingers, whereas residues in the C-terminal extension following the third zinc finger bind in the opposing minor groove and are required for high-affinity binding. The C-terminal region is disordered in the free protein and adopts an ordered structure upon binding to DNA. The structures of these Kaiso complexes provide insights into the mechanism by which a zinc finger protein can recognize mCpG sites as well as a specific, nonmethylated regulatory DNA sequence.protein-DNA interaction | NMR spectroscopy | X-ray crystallography | folding upon binding | intrinsic disorder I n eukaryotes, DNA methylation is a common epigenetic modification that is central to the maintenance of genome stability, gene silencing, genomic imprinting, development, and disease (1, 2). Methyl-CpG-binding proteins (MBPs) mediate these processes by binding to methylated DNA signals and recruiting chromatin remodeling corepressor complexes, resulting in compaction of chromatin into its transcriptionally inactive state (3). To date, three classes of MBPs that recognize 5-methyl cytosine (5mC) have been identified. The SRA domain family has specificity for hemimethylated sites and is required for maintenance methylation during DNA replication (4). In contrast, the methyl CpG-binding domain (MBD) and Kaiso families of MBPs function as essential mediators of epigenetically controlled gene silencing by recognizing symmetrically methylated CpG sites (5). Kaiso is a MBP belonging to the BTB/POZ (broad complex, tramtrak, bric à brac/pox virus and zinc finger) subfamily of transcription factors that recognize cognate DNA sequences through a C-terminal zinc finger domain; the N-terminal BTB/POZ domain mediates protein-protein interactions (6). Kaiso is a POZ protein that participates in both methyl-dependent and sequence-specific transcriptional repression, using its three Cys 2 His 2 zinc fingers to recognize either two consecutive symmetrically methylated CpG dinucleotides (mCpG) (7, 8) or a TCCTGCNA consensus (termed "KBS") (9). Although originally it was reported that Kaiso only requires zinc fingers 2 and 3 for DNA recog...

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

Buck‐Koehntop

Stanfield

Ekiert

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

160

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“…Several lines of evidence suggest roles for p120 and Kaiso in canonical and noncanonical Wnt signaling (19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

Smalley-Freed¹,

Ефимов²,

Burnett³

et al. 2010

J. Clin. Invest.

125

152

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Epithelial-cadherin (E-cadherin) is a master organizer of the epithelial phenotype. Its function is regulated in part by p120-catenin (referred to herein as p120), a cytoplasmic binding partner that directly regulates cadherin stability. As it has been suggested that cadherins have a role in inflammatory bowel disease (IBD), we sought to investigate this further by assessing the effect of p120 deficiency in mouse small intestine and colon. p120 conditional KO mice were superficially normal at birth but declined rapidly and died within 21 days. Cellcell adhesion defects and inflammation led to progressive mucosal erosion and terminal bleeding, similar to what is observed in a dominant-negative cadherin mouse model of IBD. Additionally, selective loss of adherens junctions and accumulation of atypical COX-2-expressing neutrophils in p120-null areas of the colon were observed. To elucidate the mechanism, direct effects of p120 deficiency were assessed in vitro in a polarizing colon cancer cell line. Notably, transepithelial electrical resistance was dramatically reduced, neutrophil binding was increased 30 fold, and levels of COX-2, an enzyme associated with IBD, were markedly increased in neutrophils. Our data suggest that p120 loss disrupts the neonatal intestinal barrier and amplifies neutrophil engagement and that these changes lead to catastrophic inflammation during colonization of the neonatal gut with bacteria and other luminal antigens. Thus, we conclude that p120 has an essential role in barrier function and epithelial homeostasis and survival in the intestine.

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“…These interactions are important for the epigenetic silencing of tumor suppressor genes, which is an essential role of Kaiso in colon cancer development processes (Lopes et al, 2008).…”

Section: Wwwintechopencommentioning

confidence: 99%

Kaiso and Prognosis of Cancer in the Current Epigenetic Paradigm

Cofre¹

2012

Cancer Prevention - From Mechanisms to Translational Benefits

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Kaiso Contributes to DNA Methylation-Dependent Silencing of Tumor Suppressor Genes in Colon Cancer Cell Lines

Cited by 108 publications

References 29 publications

Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

Kaiso and Prognosis of Cancer in the Current Epigenetic Paradigm

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