PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer

Yu, Jack; Koujak, Susan; Nagase, Satoru; Li, C. M.; Su, Tao; Wang, Xin; Keniry, Megan; Memeo, Lorenzo; Rojtman, Albert; Mansukhani, Mahesh; Hibshoosh, Hanina; Tycko, Benjamin; Parsons, Ramon

doi:10.1038/onc.2008.101

Cited by 128 publications

(144 citation statements)

References 30 publications

(30 reference statements)

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“…We focused on the CDKN2B, 6 MLF-1, 30 PCDH8, 31 and HOXD8 32 genes that have tumor suppressor functions and were found to be hypermethylated with lower expression in both patients with MCL and MCL cell lines compared with NBCs. There have been large differences in the reported proportions of patients with MCL having hypermethylated CDKN2B, from 9% 7 to 62% 6 despite the use of identical PCR primers.…”

Section: Discussionmentioning

confidence: 99%

“…6 Protocadherin 8 (PCDH8) and homeobox D8 (HOXD8) have been found to be inactivated by methylation in breast cancer. 31,32 Cyclin-dependent kinase 5 (CDK5) plays a role in the DNA damage response and cell cycle checkpoint activation in breast cancer. 28 HDAC inhibitor HDAC1 26 and the transcription factor NOTCH1 27 are known therapeutic targets for the treatment of B-and T-cell malignancies.…”

Section: Primary Samples Have Distinct Genomic Methylation Profilmentioning

confidence: 99%

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Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Leshchenko

Kuo

Shaknovich

et al. 2010

Blood

127

102

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IntroductionMantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy accounting for 5% of non-Hodgkin lymphomas (NHLs). MCL arises from naive B cells (NBCs) in the mantle zone of lymph node follicles and is characterized by the t(11,14) chromosomal translocation leading to overexpression of cyclin D1 (CCND1). 1 However, murine models overexpressing CCND1 in the absence of other oncogenes, such as MYC, do not develop lymphoma, 2 implying that additional pathogenic mechanisms are involved in MCL. Cip/Kip proteins have an important role in the formation of active CDK4/cyclin D complexes. In NHLs other than MCL, p27(Kip) protein expression is inversely related to the proliferation activity of the tumors. 3 Apoptosis-related genes such as BCL2 have also been found to be altered in MCL with the use of different approaches. Homozygous deletions of BIM, a member of the BCL2 family, have also been found in MCL. 4 Epigenetic changes, such as methylation of gene promoters, have been shown to contribute to the pathogenesis of both solid and hematologic malignancies. 5 Single-locus studies analyzing methylation in MCL patient samples have shown hypermethylation of key genes, such as cell-cycle regulators p14 ARF and CDKN2A,6,7 protein phosphatase SHP-1 8 and Rho-adenosine triphosphatase PARG-1. 9 However these studies did not compare the methylation to NBCs, the normal counterparts of these malignant cells. 10 Several lines of evidence conclusively show NBCs to be the cell of origin of MCL, including immunoglobulin heavy chain mutation status, t (11,14) chromosomal breakpoint analysis, 11 and gene expression microarrays. 12,13 To develop a more comprehensive understanding of aberrant DNA methylation in MCL, we performed a genomewide analysis of MCL DNA methylation and gene expression with the use of purified normal NBCs as controls. We report that promoter DNA methylation is aberrantly distributed in the MCL genome compared with normal NBCs, and we identified aberrantly hypermethylated and hypomethylated genes that provide a basis for rational targeted therapy in this disease. Methods Patient samplesTissues and blood samples were obtained from patients newly diagnosed with MCL before any treatment after informed consent in accordance with the Declaration of Helsinki. Sample collection and laboratory studies were in compliance with institutional review board and Helsinki protocols. CD19 ϩ cells from 22 patients treated at the National Institutes of Health were purified by magnetic bead sorting from peripheral blood or pheresis products before freezing to ensure greater than 90% purity for HpaII tiny The publisher or recipient acknowledges right of the US government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accorda...

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Section: Discussionmentioning

confidence: 99%

Section: Primary Samples Have Distinct Genomic Methylation Profilmentioning

confidence: 99%

Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Leshchenko

Kuo

Shaknovich

et al. 2010

Blood

127

102

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“…There is increasing evidence that protocadherins can function as tumour suppressors. Protocadherins 10 and 20 are epigenetically silenced in nasopharyngeal and lung cancers (Imoto et al, 2006;Ying et al, 2006), and recently it has been reported that PCDH8 is methylated in mantle cell lymphoma and breast cancer (Yu et al, 2008;Leshchenko et al, 2010). Yu et al found that reexpressing wild-type PCDH8 in a breast cancer cell line inhibited cell migration.…”

Section: Ct Bstu1mentioning

confidence: 99%

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

et al. 2010

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The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with highdensity expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P ¼ 0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.

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“…So far, many genes have been identified as undergoing methy lation changes during tumorigenesis in many types of cancer. Wellknown tumor suppressors in this category in breast cancer are RASSF1A, BRCA1, PCDH8, and 15-Hydroxyprostaglandin (5)(6)(7)(8). Proto-oncogenes, on the other hand, undergo hypomethylation to contribute to carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Differential methylation hybridization profiling identifies involvement of STAT1-mediated pathways in breast cancer

Kim

Kang

Kim³

et al. 2011

Int J Oncol

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Abstract. Many cancer-related genes are regulated by an epigenetic mechanism through modification of the methylation status of CpG sites at the promoter. This study was carried out at a genome-wide scale to mine genes in which the methylation of CpG sites is altered in breast cancer tissues. Differential methylation hybridization analysis was conducted using a chromosomal DNA mixture of ten normal and cancer tissue sets. A CpG microarray harboring 237,220 CpG sites of the whole genome was interrogated and the resulting methylation level differences, as well as the RNA expression differences, between the normal and cancer sets for selected genes were verified in breast cell lines by methylation-specific PCR and real-time PCR analyses. As a result, we identified and verified novel genes that were hypermethylated in breast cancer, such as NRN1, CA5B and RPIA. Pathway analysis of the genes with altered methylation patterns identified the involvement of a differentiation-related network of genes whose activity may be heavily regulated by STAT1 in breast tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to STAT1-dependent cellular differentiation may be intimately involved in breast carcinogenesis. These findings lend credence to the possibility of using tumor-specific alterations in methylation patterns as biomarkers in estimating prognosis and assessing treatment options for breast cancer.

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PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer

Cited by 128 publications

References 30 publications

Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Differential methylation hybridization profiling identifies involvement of STAT1-mediated pathways in breast cancer

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