HOX gene clusters are hotspots of de novo methylation in CpG islands of human lung adenocarcinomas

Shiraishi, Masahiko; Sekiguchi, Azumi; Oates, Adam; Terry, M. C.; Miyamoto, Yuji

doi:10.1038/sj.onc.1205453

Cited by 63 publications

(45 citation statements)

References 19 publications

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“…Several homeobox genes are methylated in tumors of various histological origins. For example, methylation of HOXB13 occurs in 30% of renal cell carcinomas (27), and methylation of genes in the HOXA and HOXD clusters was reported in lung cancer (28). The HOXA5 promoter region was methylated in 16 of 20 p53-negative breast tumor specimens (29).…”

Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

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

260

221

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De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX, LHX, PAX, DLX, and Engrailed, were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancerassociated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7-and HOXA9-associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.DNA methylation ͉ HOX genes ͉ chromatin ͉ Polycomb

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Section: Discussionmentioning

confidence: 99%

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Rauch¹,

Wang²,

Zhang³

et al. 2007

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

260

221

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“…Homeobox genes are frequently down-regulated in association with aberrant methylation in human cancer cells (10) and the HOX gene clusters are a hotspot of de novo methylation in lung cancers (11). In addition to targeted DNA methylation changes in response to external stimuli, random DNA methylation changes have been shown to occur during aging of organisms in several tissue types (12,13).…”

Section: Chromatin Remodeling and Disease Statesmentioning

confidence: 99%

Developmental Origins of β-Cell Failure in Type 2 Diabetes: The Role of Epigenetic Mechanisms

Simmons

2007

Pediatr Res

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Intrauterine growth retardation (IUGR) has been linked to later development of type 2 diabetes in adulthood. An abnormal metabolic intrauterine milieu affects the development of the fetus by permanently modifying gene expression of susceptible cells. Altered gene expression persists after birth, suggesting that an epigenetic mechanism may be responsible for changes in transcription. Uteroplacental insufficiency (IUGR) is associated with hypomethylation and hyperacetylation of genomic DNA in brain and liver of IUGR fetal and juvenile rats. These findings are associated with zinc deficiency that often accompanies fetal growth retardation. Studies in the IUGR rat also demonstrate that an abnormal intrauterine environment induces epigenetic modifications of key genes regulating ␤-cell development and experiments directly link chromatin remodeling to suppression of transcription. Dietary protein restriction of pregnant rats causes fetal growth retardation and is associated with hypomethylation of the glucocorticoid receptor (GR) and PPAR␥ genes in liver of the offspring. It is postulated that these epigenetic changes result in the observed increase in gene expression of GR and PPAR␥. Future research will be directed at elucidating the mechanisms underlying epigenetic modifications in offspring. A n adverse intrauterine milieu impacts the development of the fetus by modifying gene expression in both pluripotential cells or terminally differentiated, poorly replicating cells. The long-range effects on the offspring (into adulthood) depend upon the cells undergoing differentiation, proliferation, and/or functional maturation at the time of the disturbance in maternal fuel economy. Permanent alterations to the phenotype of the offspring suggest that fetal growth retardation is associated with stable changes in gene expression. In this article, a general review of epigenetics will be provided and the possible causal role of chromatin remodeling in the development of type 2 diabetes will be discussed. CHROMATIN STRUCTURE, DNA METHYLATION, AND GENE EXPRESSIONEpigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene activity states from one generation of cells to the next. Excellent reviews on this topic appear frequently, reflecting the rapid advances of knowledge in the field (1-4). Epigenetic states can be modified by environmental factors, which may contribute to the development of abnormal phenotypes. There are at least two distinct classes of epigenetic information that can be inherited with chromosomes. One class of epigenetic control of gene expression involves changes in chromatin proteins, usually involving modifications of histone tails. In eukaryotes, DNA is assembled with histones to form the nucleosome, in which DNA is wrapped approximately two turns around an octameric complex composed of two molecules of each of the four histones H2A, H2B, H3, and H4. The amino termini of histones can be modified by acetylation, methylation, sumoylation, phosphorylation, g...

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“…In addition to their roles in development, numerous Hox genes (HoxB13, HoxA5 and HoxC6) have been found to be expressed aberrantly in a variety of solid tumors, including breast, colon and prostate cancers (16)(17)(18)(19)(20). Emerging evidence suggests that the expression of Hox genes is under epigenetic control (19)(20)(21)(22). For example, HoxA5 is suppressed in breast cancer through promoter methylation, and its suppression is correlated with the loss of p53 expression (20).…”

Section: Introductionmentioning

confidence: 99%

“…For example, HoxA5 is suppressed in breast cancer through promoter methylation, and its suppression is correlated with the loss of p53 expression (20). Studies also demonstrate that CpG islands (CpGIs) in the promoters of Hox genes are commonly methylated in lung cancer (21,22). The dysregulation of Hox genes may affect various pathways that play critical roles in tumorigenesis and cancer metastasis (19).…”

Section: Introductionmentioning

confidence: 99%

Homeobox D10 Gene, a Candidate Tumor Suppressor, Is Downregulated through Promoter Hypermethylation and Associated with Gastric Carcinogenesis

Wang

Chen

Xue

et al. 2011

Mol Med

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Homeobox D10 (HoxD10 ) gene plays a critical role in cell differentiation and morphogenesis during development. However, the function of HoxD10 in tumor progression remains largely unknown. We demonstrate that the expression of HoxD10 is commonly downregulated in gastric cancer tissues (n = 33) and cell lines (n = 8) relative to normal stomach tissues. Functionally, reexpression of HoxD10 results in significant inhibition of cell survival, induction of cell apoptosis, and impairment of cell migration and invasion. Moreover, ectopic expression of HoxD10 suppresses gastric tumor growth in a mouse xenograft model. To identify target candidates of HoxD10, we performed cDNA microarray and showed that HoxD10 regulates multiple downstream genes including IGFBP3. Reintroduction of HoxD10 transcriptionally upregulates IGFBP3, activates caspase 3 and caspase 8, and subsequently induces cell apoptosis. Methylation specific PCR revealed that HoxD10 promoter DNA was hypermethylated in gastric cancer cell lines. Additionally, 5-aza demethylation treatment could transiently reactivate the expression of HoxD10 in gastric cancer cells. HoxD10 promoter methylation frequently was detected in gastric cancer tissues obtained from endoscopic biopsies (85.7%, 24/28) and surgically resected samples (82.6%, 57/69). Intestinal metaplasia tissues showed a 60% methylation rate (18/30), but no detectable methylation in normal stomach tissues (0%, 0/10). Taken together, our results suggest that HoxD10 functions as a candidate tumor suppressor in gastric cancer, which is inactivated through promoter hypermethylation.

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HOX gene clusters are hotspots of de novo methylation in CpG islands of human lung adenocarcinomas

Cited by 63 publications

References 19 publications

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

Developmental Origins of β-Cell Failure in Type 2 Diabetes: The Role of Epigenetic Mechanisms

Homeobox D10 Gene, a Candidate Tumor Suppressor, Is Downregulated through Promoter Hypermethylation and Associated with Gastric Carcinogenesis

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