Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer

Kim, Myoung Sook; Lebron, Cinthia; Nagpal, Jatin; Chae, Young Kwang; Chang, Xiaofei; Huang, Yiping; Chuang, Tony Chih-Yuan; Yamashita, Keishi; Trink, Barry; Ratovitski, Edward A.; Califano, Joseph A.; Sidransky, David

doi:10.1016/j.bbrc.2008.03.026

Cited by 126 publications

(146 citation statements)

References 15 publications

(24 reference statements)

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“…In breast carcinoma, the methylation status of DFNA5 was correlated with lymph node metastasis. 15 These recent data also explain earlier findings that were not well understood at the time, such as the increased resistance to the chemotherapeutic reagent etoposide in melanoma cells with decreased transcription of DFNA5, 11 or the finding that DFNA5 is induced by p53 through a p53-binding site located in intron 1. 12 Webb et al 17 demonstrated that DFNA5 mRNA expression increased after treatment of human acute lymphoblastic leukemia cell lines with the glucocorticoid dexamethasone.…”

Section: Introductionsupporting

confidence: 68%

“…Methylation of the 5¢-flanking region of DFNA5, as frequently observed in gastric, colorectal and breast carcinoma, [13][14][15][16] may be a way to prevent the apoptotic actions of DFNA5. We believe that our description of the apoptosis-inducing mechanism of DFNA5 contributes to the growing evidence that DFNA5 may be a tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 98%

“…However, since its identification, the small number of papers published on DFNA5 almost all point to a possible involvement in cancer biology. [10][11][12][13][14][15][16] Especially during the last 3 years, DFNA5 emerged from several genomic screens identifying new tumor suppressor genes. Further analysis showed that the DFNA5 gene is epigenetically inactivated in several types of cancer, including gastric, colorectal and breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Further analysis showed that the DFNA5 gene is epigenetically inactivated in several types of cancer, including gastric, colorectal and breast cancer. [13][14][15][16] Epigenetic silencing through methylation was found in 52-65% of primary tumors. In addition, in vitro studies showed that cell invasion, colony numbers, colony size and cell growth increased in cell lines after DFNA5 knockdown.…”

Section: Introductionmentioning

confidence: 99%

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The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL. Keywords: tumor suppressor; hearing loss; apoptosis; dfna5; cancer; GSEA INTRODUCTION DFNA5 first was discovered in a Dutch family with autosomal dominant hearing loss (HL). 1 Not much was known concerning its cellular function and how its function was related to HL. Recently, a novel mutation in DFNA5 has been identified in a Korean family, totaling five families with DFNA5 HL. 2 These families all have different genomic DFNA5 mutations, but in each case the DFNA5 mRNA transcript skips exon 8, resulting in a frameshift and a premature truncation of the protein. [1][2][3][4][5] These findings have led to the hypothesis that DFNA5-associated HL is attributable to a highly specific gain-of-function mutation, in which skipping of one exon causes disease while mutations in other parts of this gene may not result in HL at all. Further experimental evidence for this hypothesis was provided by the finding that transfection of mutant DFNA5 causes cell death in both yeast 6 and mammalian 7 cells and by the discovery of a new DFNA5 mutation. 8 The latter mutation truncated the protein in the fifth exon, but did not segregate with HL and was present in family members with normal hearing. The hypothesis was further corroborated by a mouse that lacked the Dfna5 protein. This knockout (KO) mouse did not display any HL and, as a consequence, was not a suitable animal model to study DFNA5-associated HL. 9 To date, little information is available on the physiological function of DFNA5. However, since its identification, the small num...

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Section: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

et al. 2011

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“…85,86 Cancer-specifi c methylation is, however, a rather rare event, and is presumably only recognized in the genes with robust tumor suppressive function. [87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103] Methylation of CpG islands for normal genes occurs at random, but hypomethylation is more common in cancer cells than in normal tissues. 104,105 As a result, gene promoter methylation that is related to cancer development or progression is relatively rare, and it is worth further investigation to determine whether these methylated genes can be used as candidate biomarkers and therapeutic targets.…”

Section: Epigenetic Alterations In Gastric Cancermentioning

confidence: 99%

Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications

2010

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Knowledge about the molecular profile of tumor tissues is crucial to effectively target cancer cells, because cancer is a genetic disease that involves multiple genetic and epigenetic alterations. Prominent aberrations include gene mutation, amplification, loss or deletion, as well as epigenetic alterations of the promoter DNA CpG islands. All of these aberrations can lead to dynamic changes in cancer cells, as demonstrated using resected tumor samples. There are two distinct pathological types of gastric cancer: the diffuse type and the intestinal type of gastric cancer. Diffuse type gastric cancer harbors aberrations in the FGFR2/ErbB3/PI3 kinase pathway, while intestinal type gastric cancer has an activated ErbB2 oncogenic pathway. On the other hand, the prometastatic oncogene PRL-3 is commonly activated in both types of advanced gastric cancer, and might represent a relevant therapeutic target for gastric cancer with lymph node metastasis or peritoneal dissemination. Numerous tumor suppressor genes can inhibit such oncogenic pathways, and DNA methylation in CpG islands of gene promoters is frequently found to suppress the expression of such genes in gastric cancer. Helicobacter pylori infection in normal gastric mucosa may cause p53 mutations through activation of activation-induced cytidine deaminase (AID) and/or promoter DNA methylation of E-cadherin, an initiator of gastric cancer, and such abnormalities are found even in the precancerous stage of gastric carcinogenesis. In addition, it has been demonstrated that there are highly relevant methylation genes involved in cancer (HRMGs) that exhibit very frequent cancer-specific methylation in gastric cancer. Such genes are potential targets for cancer treatment, and might also serve as biomarkers of gastric cancer for either the diagnosis or for determining the prognosis or the response to treatment.

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Epigenetic Medicine

Jirtle¹,

Bernal²,

Skaar³

2011

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer

Cited by 126 publications

References 15 publications

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein

Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications

Epigenetic Medicine

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