Cancer specific promoter CpG Islands hypermethylation of HOP homeobox (HOPX) gene and its potential tumor suppressive role in pancreatic carcinogenesis

Waraya, Mina; Yamashita, Keishi; Katoh, Hiroshi; Ooki, Akira; Kawamata, Hiroshi; Nishimiya, Hiroshi; Nakamura, Kazunori; Ema, Akira; Watanabe, Masahiko

doi:10.1186/1471-2407-12-397

Cited by 40 publications

(45 citation statements)

References 29 publications

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“…One of this genes is HOP which encodes the Hsp70-Hsp90 Organizing Protein (gene ID 84525), and abnormal methylation of this gene has been recently associated with different types of cancer. [25][26][27] The differential methylation of HOP in the ART group was confirmed using a pyrosequencing assay (Fig. 5).…”

Section: Does the Association Of Art With Global Methylation Vary Witmentioning

confidence: 76%

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

et al. 2015

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Data linking assisted reproductive technologies (ART) with aberrant DNA methylation is limited and inconclusive. In addition, most studies to date have analyzed only a small number of CpG sites and focused on methylation changes in placentas, while data on cord blood are scarce. Our aim was to compare DNA methylation in cord blood samples from ART (N D 10) and control pregnancies (N D 8) using a genome-wide approach with the Illumina Ò Infinium Human Methylation27 array, which interrogates 27,578 CpG sites. A total of 733 (2.7%) of the CpG sites were significantly differentially methylated between the 2 groups (P < 0.05), with an overall relative hypomethylation in the ART group (P < 0.001). Differences in DNA methylation were more pronounced for CpG sites in certain types of genomic locations and were related to baseline methylation levels and distance from CpG islands and transcription start sites. ART was associated with significantly higher variation in DNA methylation, suggesting that differences in DNA methylation between cases and controls may result from stochastic (or random) genome-wide changes in DNA methylation in ART pregnancies. We identified 24 candidate genes with 2 or more CpG sites that were significantly different between the IVF and control groups. The current study provides support for the hypothesis that ART or associated subfertility may be associated with genome-wide changes in DNA methylation, and these changes appear to be, at least in part, due to epigenetic instability in ART pregnancies. Further studies are required in order to determine the extent to which such ART-related epigenetic instability may have phenotypic consequences.

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Section: Does the Association Of Art With Global Methylation Vary Witmentioning

confidence: 76%

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

et al. 2015

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“…The loss of HOPX expression in other malignancies, such as gastric, pancreatic, esophageal, colorectal and lung cancers, is attributed to the hypermethylation of HOPX-β promoter810112021. In the present study, we show that the HOPX-β promoter is hypermethylated in approximately 50% of OSCC and NPC cell lines and that treatment of an OSCC cell line with a demethylating drug restored HOPX expression, suggesting that promoter methylation is in part responsible for the loss of HOPX expression in HNSCCs.…”

Section: Discussionmentioning

confidence: 99%

“…However, recent analysis of NCBI reference sequences indicates that there are five transcripts that encode three different proteins9, although the expression of these transcripts in different tissues has not yet been examined. The HOPX-β promoter contains CpG islands that are methylated in various cancers leading to down-regulation of HOPX expression, strongly suggesting that HOPX functions as a tumour suppressor81011.…”

mentioning

confidence: 99%

HOPX functions as a tumour suppressor in head and neck cancer

Yap

Lai

Patmanathan

et al. 2016

Sci Rep

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Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis.

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“…1A) and found a significant decrease in the HOPX mRNA level in PR9692-E9 cells. Transcriptional suppression of HOPX expression has repeatedly been correlated with promoter hypermethylation (15,16,23,24). To test the epigenetic character of HOPX suppression, we examined the HOPX methylation status in PR9692 and PR9692-E9 cells by bisulfite sequencing.…”

Section: Decreased Hopx Expression In the Nonmetastatic Pr9692-e9 Cellsmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

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Cancer specific promoter CpG Islands hypermethylation of HOP homeobox (HOPX) gene and its potential tumor suppressive role in pancreatic carcinogenesis

Cited by 40 publications

References 29 publications

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

Comparison of genome-wide and gene-specific DNA methylation between ART and naturally conceived pregnancies

HOPX functions as a tumour suppressor in head and neck cancer

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

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