Epigenetic inactivation of CHFR in human tumors

Toyota, Minoru; Sasaki, Yasushi; Satoh, Ayumi; Ogi, Kazuhiro; Kikuchi, Takefumi; Suzuki, Hiromu; Mitsuya, Hiroaki; Tanaka, Nobuyuki; Itoh, Fumio; Issa, Jean–Pierre J.; Jair, Kam Wing; Schuebel, Kornel E.; Imai, Kohzoh; Tokino, Takashi

doi:10.1073/pnas.1337066100

Cited by 186 publications

(193 citation statements)

References 24 publications

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“…The fact that in methylated cell lines BNIP3 expression was restored by 5-aza-dC, a methyltransferase inhibitor, confirms that inactivation of the gene was caused by DNA methylation and not by, for example, the loss of transcription factors. DNMT1 and DNMT3b are known to catalyse DNA methylation in cancer cells (Rhee et al, 2002;Toyota et al, 2003); the mechanism by which DNA methylation represses gene expression is not fully understood, however, although histone deacetylation reportedly plays a key role (Bird and Wolffe, 1999;Cameron et al, 1999;Nguyen et al, 2001). Consistent with that finding, our ChIP assays showed histone H3 to be deacetylated in cell lines where BNIP3 is silent.…”

Section: Discussionsupporting

confidence: 85%

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

et al. 2005

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Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2 0 -deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5 0 region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5 0 CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

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Section: Discussionsupporting

confidence: 85%

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

et al. 2005

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“…The two CRC cell lines (RKO and DKO2) used were described previously (Toyota et al, 2003). All of the cell lines were cultured in the appropriate medium.…”

Section: Cell Lines and Tissue Specimensmentioning

confidence: 99%

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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Although mutation of APC or CTNNB1 (b-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a b-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. British Journal of Cancer (2008) Wnt ligands are secreted proteins that bind to transmembrane receptors in the Frizzled (Fz) family. During normal developmental processes, the resultant Wnt signalling plays essential roles in the regulation of cell proliferation, patterning and fate determination (Cadigan and Nusse, 1997). The binding of Wnt to Fz leads to dephosphorylation and stabilisation of b-catenin, enabling it to be translocated into the nucleus, where it interacts with members of the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family of transcription factors to stimulate the expression of target genes. This signalling pathway is strongly implicated in tumorigenesis; indeed, the first mammalian Wnt isoform was identified based on its ability to promote mouse mammary tumorigenesis (Polakis, 2000). In addition, aberrant nuclear and cytoplasmic localisation of b-catenin is frequently observed in human breast cancer (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). In contrast to colorectal cancer (CRC), however, mutation of APC, AXIN or CTNNB1 (b-catenin) is rare in breast cancer, indicating that other mechanisms are responsible for the activation of b-catenin. These mechanisms could include increased expression of Wnt ligand (Huguet et al, 1994;Dale et al, 1996;Bui et al, 1997) and/or the loss of Wnt antagonists.Several classes of secreted Wnt antagonists are known, including the Cerberus, Wnt inhibitory factor 1, secreted frizzled-related protein (SFRP) and the Dickkopf (DKK) families (Kawano and Kypta, 2003). The SFRP family is comprised of five secreted glycopr...

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“…Thirteen GC cell lines (MKN1, MKN7, MKN28, MKN45, MKN74, SH101, SNU1, SNU638, JRST, KatoIII, AZ521, NUGC3 and NUGC4) and two CRC cell lines (HCT116 and DLD1) were obtained as described previously Toyota et al, 2003). Three others (AGS, NCI-N87 and SNU16) were obtained from the American Type Culture Collection (Manassas, VA, USA).…”

Section: Cell Lines and Tissuesmentioning

confidence: 99%

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

et al. 2007

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Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (b-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear b-catenin accumulation (13/15; 87%) and detected the active form of b-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/ 16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%), and treatment with the DNA methyltransferase inhibitor 5-aza-2 0 -deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.

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Epigenetic inactivation of CHFR in human tumors

Cited by 186 publications

References 24 publications

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

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