Research IndicatorsGraph generated 25 June 2015 using data from PubMed using criteria.
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Specific Cancers (2)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: CHD5 (cancer-related)
Loss of the chromatin remodeling ATPase CHD5 has been linked to the progression of neuroblastoma tumors, yet the underlying mechanisms behind the tumor suppressor role of CHD5 are unknown. In this study, we purified the human CHD5 complex and found that CHD5 is a component of the full NuRD transcriptional repressor complex, which also contains methyl-CpG binding proteins and histone deacetylases. The CHD5/NuRD complex appears mutually exclusive with the related CHD4/NuRD complex as overexpression of CHD5 results in loss of the CHD4 protein in cells. Following a search for genes that are regulated by CHD5 in neuroblastoma cells, we found that CHD5 binds to and represses the G2/M checkpoint gene WEE1. Reintroduction of CHD5 into neuroblastoma cells represses WEE1 expression, demonstrating that CHD5 can function as a repressor in cells. A catalytically inactive mutant version of CHD5 is able to associate with a NuRD cofactor but fails to repress transcription. Our study shows that CHD5 is a NuRD-associated transcriptional repressor and identifies WEE1 as one of the CHD5-regulated genes that may link CHD5 to tumor suppression.
Zhao R, Wang N, Huang H, et al.CHD5 a tumour suppressor is epigenetically silenced in hepatocellular carcinoma.
Liver Int. 2014; 34(6):e151-60 [PubMed
] Related Publications
BACKGROUND: Chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a potent tumour suppressor by acting as a master regulator of a tumour-suppressive network. Its inactivation resulted from aberrant methylation in the promoter occurs in several types of human malignancy and is associated with malignant tumour behaviour. In human hepatocellular carcinoma (HCC), CHD5 gene expression, methylation status and tumour-suppressive function have not been elucidated.
AIMS: In this study, we focused on the epigenetic modification and tumour-suppressive mechanism of CHD5 gene in HCC.
METHODS: CHD5 expression in nine HCC cell lines and 30 pairs of HCC specimens and adjacent non-cancerous tissues were analysed by quantitative reverse transcription PCR and Western blotting. Methylation-specific sequencing and methylation-specific PCR were performed to examine DNA methylation status of the CHD5 promoter in HCC cell lines and samples. The effect of CHD5 restoration on proliferation, colony formation, senescence, apoptosis and tumourigenicity were examined.
RESULTS: CHD5 expression was sinificantly down-regulated in HCC cell lines and tissues examined, and the -841 to -470 region of CHD5 promoter was hypermethylated in these samples. Treatment with DNA methyltransferase inhibitor 5-aza-2-deoxycytidine resulted in a striking regional demethylation of the -841 to -470 region of CHD5 promoter and an increase in CHD5 expression. The restoration of CHD5 expression inhibited tumour cell proliferation, colony formation and tumourigenicity and caused cellular senescence.
CONCLUSIONS: Our findings demonstrate that CHD5 is a potential tumour suppressor gene epigenetically silenced in HCC.
Chromodomain helicase DNA binding protein 5 (CHD5) was previously proposed to function as a potent tumor suppressor by acting as a master regulator of a tumor-suppressive network. CHD5 is down-regulated in several cancers, including leukemia and is responsible for tumor generation and progression. However, the mechanism of CHD5 down-regulation in leukemia is largely unknown. In this study, quantitative reverse-transcriptase polymerase chain reaction and western blotting analyses revealed that CHD5 was down-regulated in human leukemia cell lines and samples. Luciferase reporter assays showed that most of the baseline regulatory activity was localized from 500 to 200 bp upstream of the transcription start site. Bisulfite DNA sequencing of the identified regulatory element revealed that the CHD5 promoter was hypermethylated in human leukemia cells and samples. Thus, CHD5 expression was inversely correlated with promoter DNA methylation in these samples. Treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) activates CHD5 expression in human leukemia cell lines. In vitro luciferase reporter assays demonstrated that methylation of the CHD5 promoter repressed its promoter activity. Furthermore, a chromatin immunoprecipitation assay combined with qualitative PCR identified activating protein 2 (AP2) as a potential transcription factor involved in CHD5 expression and indicated that treatment with DAC increases the recruitment of AP2 to the CHD5 promoter. In vitro transcription-factor activity studies showed that AP2 over-expression was able to activate CHD5 promoter activity. Our findings indicate that repression of CHD5 gene expression in human leukemia is mediated in part by DNA methylation of its promoter.
CHD5 was first identified because of its location on 1p36 in a region of frequent deletion in neuroblastomas. CHD5 (chromodomain-helicase-DNA-binding-5) is the fifth member of a family of chromatin remodeling proteins, and it probably functions by forming a nucleosome remodeling and deacetylation (NuRD) complex that regulates transcription of particular genes. CHD5 is preferentially expressed in the nervous system and testis. On the basis of its position, pattern of expression, and function in neuroblastoma cells and xenografts, CHD5 was identified as a tumor suppressor gene (TSG). Evidence soon emerged that CHD5 also functioned as a TSG in gliomas and a variety of other tumor types, including breast, colon, lung, ovary, and prostate cancers. Although one copy of CHD5 is deleted frequently, inactivating mutations of the remaining allele are rare. However, DNA methylation of the CHD5 promoter is found frequently, and this epigenetic mechanism leads to biallelic inactivation. Furthermore, low CHD5 expression is strongly associated with unfavorable clinical and biologic features as well as outcome in neuroblastomas and many other tumor types. Thus, based on its likely involvement as a TSG in neuroblastomas, gliomas, and many common adult tumors, CHD5 may play an important developmental role in many other tissues besides the nervous system and testis.
Hall WA, Petrova AV, Colbert LE, et al.Low CHD5 expression activates the DNA damage response and predicts poor outcome in patients undergoing adjuvant therapy for resected pancreatic cancer.
Oncogene. 2014; 33(47):5450-6 [PubMed
] Related Publications
The DNA damage response (DDR) promotes genome integrity and serves as a cancer barrier in precancerous lesions but paradoxically may promote cancer survival. Genes that activate the DDR when dysregulated could function as useful biomarkers for outcome in cancer patients. Using a siRNA screen in human pancreatic cancer cells, we identified the CHD5 tumor suppressor as a gene, which, when silenced, activates the DDR. We evaluated the relationship of CHD5 expression with DDR activation in human pancreatic cancer cells and the association of CHD5 expression in 80 patients with resected pancreatic adenocarcinoma (PAC) by immunohistochemical analysis with clinical outcome. CHD5 depletion and low CHD5 expression in human pancreatic cancer cells lead to increased H2AX-Ser139 and CHK2-Thr68 phosphorylation and accumulation into nuclear foci. On Kaplan-Meier log-rank survival analysis, patients with low CHD5 expression had a median recurrence-free survival (RFS) of 5.3 vs 15.4 months for patients with high CHD5 expression (P=0.03). In 59 patients receiving adjuvant chemotherapy, low CHD5 expression was associated with decreased RFS (4.5 vs 16.3 months; P=0.001) and overall survival (OS) (7.2 vs 21.6 months; P=0.003). On multivariate Cox regression analysis, low CHD5 expression remained associated with worse OS (HR: 3.187 (95% CI: 1.49-6.81); P=0.003) in patients undergoing adjuvant chemotherapy. Thus, low CHD5 expression activates the DDR and predicts for worse OS in patients with resected PAC receiving adjuvant chemotherapy. Our findings support a model in which dysregulated expression of tumor suppressor genes that induce DDR activation can be utilized as biomarkers for poor outcome.
BACKGROUND: Chromodomain helicase DNA binding protein 5 (CHD5) is a family member of chromatin remodeling factors. The epigenetic silencing mechanisms of CHD5 in colorectal cancer have not been well studied.
METHODS: Here we analyzed CHD5 methylation and mRNA expression in vitro and in clinical samples from African American patients. DNA and RNA were isolated from formalin fixed paraffin embedded (FFPE) colon tissues. DNA was tested for methylation using methylation-specific polymerase chain reation (PCR) and bisulfite sequencing. RNA was used for mRNA quantification using qRT-PCR. The RKO cell line was treated with 5-Aza-dC and SAHA. RKO cells were also stably transfected with a CHD5-expressing vector. The transcriptional activity was studied in the 1 kb upstream region of the CHD5 promoter using the dual reporter assay. We performed cell proliferation, migration, and invasion assays using the RKO cell line.
RESULTS: In most adenoma samples, CHD5 expression was not detected in contrast to normal tissues. In RKO cells, CHD5 silencing was associated with DNA methylation and repressive histone modifications. CHD5 expression was restored after treatment with 5-Aza-dC and SAHA. CHD5 reactivation reduced cell proliferation, migration, and invasion. The reporter assay indicated that the main regulatory region of the CHD5 promoter is encompassed in the -489 to -823 region with important transcriptional regulatory sites (TCF/LEF, SP1, and AP-2).
CONCLUSIONS: The CHD5 gene is repressed in all types of adenomas, either epigenetically or by chromosomal deletion. CHD5 activity is regulated by DNA methylation and repressive histone modifications. CHD5 likely acts as a tumor-suppressor gene in early colorectal carcinogenesis.
Egan CM, Nyman U, Skotte J, et al.CHD5 is required for neurogenesis and has a dual role in facilitating gene expression and polycomb gene repression.
Dev Cell. 2013; 26(3):223-36 [PubMed
] Related Publications
The chromatin remodeler CHD5 is expressed in neural tissue and is frequently deleted in aggressive neuroblastoma. Very little is known about the function of CHD5 in the nervous system or its mechanism of action. Here we report that depletion of Chd5 in the developing neocortex blocks neuronal differentiation and leads to an accumulation of undifferentiated progenitors. CHD5 binds a large cohort of genes and is required for facilitating the activation of neuronal genes. It also binds a cohort of Polycomb targets and is required for the maintenance of H3K27me3 on these genes. Interestingly, the chromodomains of CHD5 directly bind H3K27me3 and are required for neuronal differentiation. In the absence of CHD5, a subgroup of Polycomb-repressed genes becomes aberrantly expressed. These findings provide insights into the regulatory role of CHD5 during neurogenesis and suggest how inactivation of this candidate tumor suppressor might contribute to neuroblastoma.
Wang L, He S, Tu Y, et al.Downregulation of chromatin remodeling factor CHD5 is associated with a poor prognosis in human glioma.
J Clin Neurosci. 2013; 20(7):958-63 [PubMed
] Related Publications
Chromodomain helicase DNA-binding protein 5 (CHD5), a member of the CHD family, is involved in key cellular processes including chromatin remodeling, cell cycle regulation, and cellular adhesion. Recent studies have demonstrated that CHD5 is the product of a novel tumor suppressor gene and is implicated in certain tumor types. However, the clinicopathological significance of CHD5 expression in human malignant gliomas remains unclear. To address this problem, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured using real-time quantitative polymerase chain reaction (RT-PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors or prognosis of glioma patients was statistically analyzed. Genetic and protein expression of CHD5 were downregulated in glioma tissues compared to corresponding non-neoplastic brain tissues (both p<0.001). Additionally, decreased expression of CHD5 in glioma was significantly associated with pathological grade (p=0.007); high pathological grade was associated with low CHD5 expression. Loss of CHD5 protein expression was also significantly correlated with a low Karnofsky performance scale score (p=0.01). Moreover, overall survival of patients with low CHD5 protein expression was dramatically shorter than those of patients with high CHD5 protein expression (p=0.003). Multivariate Cox regression analysis indicated that CHD5 expression was an independent prognostic factor for patients with gliomas (p=0.01). In conclusion, these data offer convincing evidence for the first time that CHD5 might act as a tumor suppressor in glioma, may act as a regulator of aggressive development, and is a candidate prognostic marker for this malignancy.
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.
Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer. Although CHD5 belongs to the CHD family of chromatin-remodeling proteins, whether its tumor-suppressive role involves an interaction with chromatin is unknown. Here we report that Chd5 binds the unmodified N terminus of H3 through its tandem plant homeodomains (PHDs). Genome-wide chromatin immunoprecipitation studies reveal preferential binding of Chd5 to loci lacking the active mark H3K4me3 and also identify Chd5 targets implicated in cancer. Chd5 mutations that abrogate H3 binding are unable to inhibit proliferation or transcriptionally modulate target genes, which leads to tumorigenesis in vivo. Unlike wild-type Chd5, Chd5-PHD mutants are unable to induce differentiation or efficiently suppress the growth of human neuroblastoma in vivo. Our work defines Chd5 as an N-terminally unmodified H3-binding protein and provides functional evidence that this interaction orchestrates chromatin-mediated transcriptional programs critical for tumor suppression.
Henrich KO, Schwab M, Westermann F1p36 tumor suppression--a matter of dosage?
Cancer Res. 2012; 72(23):6079-88 [PubMed
] Related Publications
A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic "two-hit" manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes.
Mallette FA, Richard SJMJD2A promotes cellular transformation by blocking cellular senescence through transcriptional repression of the tumor suppressor CHD5.
Cell Rep. 2012; 2(5):1233-43 [PubMed
] Related Publications
Senescence is a cellular response preventing tumorigenesis. The Ras oncogene is frequently activated or mutated in human cancers, but Ras activation is insufficient to transform primary cells. In a search for cooperating oncogenes, we identify the lysine demethylase JMJD2A/KDM4A. We show that JMJD2A functions as a negative regulator of Ras-induced senescence and collaborates with oncogenic Ras to promote cellular transformation by negatively regulating the p53 pathway. We find CHD5, a known tumor suppressor regulating p53 activity, as a target of JMJD2A. The expression of JMJD2A inhibits Ras-mediated CHD5 induction leading to a reduced activity of the p53 pathway. In addition, we show that JMJD2A is overexpressed in mouse and human lung cancers. Depletion of JMJD2A in the human lung cancer cell line A549 bearing an activated K-Ras allele triggers senescence. We propose that JMJD2A is an oncogene that represents a target for Ras-expressing tumors.
Li H, Xu W, Huang Y, et al.Genistein demethylates the promoter of CHD5 and inhibits neuroblastoma growth in vivo.
Int J Mol Med. 2012; 30(5):1081-6 [PubMed
] Related Publications
Neuroblastoma (NB) is a type of tumor usually found in children under 5 years of age, which originates from lesions in the nervous system and has fast growth and early transformation characteristics. Similar to other cancer types, some typical tumor suppressor genes (TSGs), such as P53 and CHD5 are silenced in NB because of high methylation at promoter zones. In the present study, our results showed that genistein, an element found in soy, is an epigenetic modifier able to decrease hypermethylation levels of CHD5, and enhances the expression of CHD5 as well as p53, possibly contributing to inhibition of NB growth in vivo and tumor microvessel formation. Furthermore, genistein acts as a DNA methyltransferase (DNMT) inhibitor to significantly decrease the expression of DNMT3b. Our study indicates that genistein plays an important role in inhibiting NB growth in vivo, probably preventing tumorigenesis risk as a kind of therapeutic agent for NB treatment in the future.
INTRODUCTION: The chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as a tumor suppressor in a mouse model. The CHD5 locus at 1p36 is deleted, and its mutation has been detected in breast cancer. We, therefore, evaluated whether CHD5 plays a role in human breast cancer.
METHODS: We screened mutations in 55 tumors, determined promoter methylation in 39 tumors, measured RNA expression in 90 tumors, analyzed protein expression in 289 tumors, and correlated expression changes with clinicopathological characteristics of breast cancer. Functional effects of CHD5 on cell proliferation, invasion and tumorigenesis were also tested.
RESULTS: Although only one mutation was detected, CHD5 mRNA expression was significantly reduced, accompanied by frequent genomic deletion and promoter methylation, in breast cancer. The extent of methylation was significantly associated with reduced mRNA expression, and demethylating treatment restored CHD5 expression. Lower CHD5 mRNA levels correlated with lymph node metastasis (P = 0.026). CHD5 protein expression was also reduced in breast cancer, and lack of CHD5 expression significantly correlated with higher tumor stage, ER/PR-negativity, HER2 positivity, distant metastasis and worse patient survival (P ≤ 0.01). Functionally, ectopic expression of CHD5 in breast cancer cells inhibited cell proliferation and invasion in vitro and tumorigenesis in nude mice. Consistent with the inhibition of invasion, CHD5 down-regulated mesenchymal markers vimentin, N-cadherin and ZEB1 in breast cancer cells.
CONCLUSION: Down-regulation of CHD5, mediated at least in part by promoter methylation, contributes to the development and progression of human breast cancer.
PURPOSE: Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma.
EXPERIMENTAL DESIGN: The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients.
RESULTS: On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P < 0.001; set 2 OS: 0.97 ± 0.02 vs. 0.61 ± 0.1, P = 0.005, EFS: 0.91 ± 0.8 vs. 0.56 ± 0.1, P = 0.005; and set 3 OS: 0.99 ± 0.01 vs. 0.56 ± 0.06, EFS: 0.96 ± 0.02 vs. 0.43 ± 0.05, both P < 0.001]. Multivariate analysis showed that the model was an independent marker for survival (P < 0.001, for all). In comparison with accepted risk stratification systems, the model robustly classified patients in the total cohort and in different clinically relevant risk subgroups.
CONCLUSION: We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems.
PURPOSE: Neuroblastomas (NBs) have genomic, biological, and clinical heterogeneity. High-risk NBs are characterized by several genomic changes, including MYCN amplification and 1p36 deletion. We identified the chromatin-remodeling gene CHD5 as a tumor suppressor gene that maps to 1p36.31. Low or absent CHD5 expression is associated with a 1p36 deletion and an unfavorable outcome, but the mechanisms of CHD5 inactivation in NBs are unknown.
EXPERIMENTAL DESIGN: We examined (i) the CHD5 sequence in 188 high-risk NBs investigated through the TARGET initiative, (ii) the methylation status of the CHD5 promoter in 108 NBs with or without 1p36 deletion and/or MYCN amplification, and (iii) mRNA expression of CHD5 and MYCN in 814 representative NBs using TaqMan low-density array microfluidic cards.
RESULTS: We found no examples of somatically acquired CHD5 mutations, even in cases with 1p36 deletion, indicating that homozygous genomic inactivation is rare. Methylation of the CHD5 promoter was common in the high-risk tumors, and it was generally associated with both 1p deletion and MYCN amplification. High CHD5 expression was a powerful predictor of favorable outcome, and it showed prognostic value even in multivariable analysis after adjusting for MYCN amplification, 1p36 deletion, and/or 11q deletion.
CONCLUSIONS: We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) high CHD5 expression is strongly correlated with favorable clinical/biological features and outcome.
BACKGROUND: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis.
METHODOLOGY/PRINCIPAL FINDINGS: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116(miR-211)) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116(miR-211) cells was upregulated by 16-fold compared to vector control cells (HCT-116(vector)). Exogenous miR-211 directly binds to the 3'-untranslated region (3'-UTR) of CHD5 mRNA, resulting in a 50% decrease in CHD5 protein level in HCT-116(miR-211) cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116(miR-211) cells were significantly higher than HCT-116(vector) cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax.
CONCLUSION/SIGNIFICANCE: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression of miR-211 promotes tumor cell growth at least in part by downregulating the expression level of the CHD5 tumor suppressor. Our results provide a better understanding of the association of between miR-211-regulated CHD5 expression and CHD5 function in colorectal tumorigenesis.
Zhao R, Yan Q, Lv J, et al.CHD5, a tumor suppressor that is epigenetically silenced in lung cancer.
Lung Cancer. 2012; 76(3):324-31 [PubMed
] Related Publications
Chromodomain helicase DNA binding protein 5 (CHD5) is a potent tumor suppressor that serves as a master regulator of a tumor-suppressive network. Examination of the role played by CHD5 in a wide range of human cancers is warranted. In this study, we focused on the epigenetic modification and tumor-suppressive role of CHD5 in lung cancer. We measured CHD5 mRNA and protein expression in lung cancer cells, lung cancer tissues, and their corresponding noncancerous lung tissues using real-time PCR and Western blot analysis. We then determined the methylation status of the CHD5 promoter in these samples using methylation-specific sequencing and analyzed CHD5 re-expression in lung cancer cells treated with or without 5-aza-2-deoxycytidine, an inhibitor of DNA methylation. Next, the lung cancer cell clones stably expressing EGFP-CHD5 protein or EGFP protein, respectively, were obtained and the effects of restored CHD5 expression on cell proliferation, colony formation, and tumorigenicity were assessed. CHD5 expression ranged from low to absent in the lung cancer cell lines and tissues examined; the CHD5 promoter was hyperethylated in these samples. Treatment with 5-aza-dC resulted in a localized decrease in methylation density and an increase in CHD5 expression. Clonogenicity and tumor growth were abrogated in A549 and H1299 cells upon restoration of CHD5 expression. A significant reduction in clonogenicity was observed; an average of 47.83 ± 4.6% reduction for A549-EGFP-CHD5 was observed compared to A549-EGFP, and an average of 56.39 ± 5.3% reduction for H1299-EGFP-CHD5 was observed compared to H1299-EGFP. A549-EGFP exhibited an average tumor size of 452.3 ± 36.5 mm(3), whereas A549-EGFP-CHD5 exhibited an average tumor size of only 57.7 ± 18.5 mm(3). Thus, our findings indicate that CHD5 is a potential tumor suppressor gene that is inactivated via an epigenetic mechanism in lung cancer.
Wong RR, Chan LK, Tsang TP, et al.CHD5 Downregulation Associated with Poor Prognosis in Epithelial Ovarian Cancer.
Gynecol Obstet Invest. 2011; 72(3):203-7 [PubMed
] Related Publications
BACKGROUND: The CHD5 gene located on 1p36 encodes a protein-chromodomain helicase DNA-binding protein 5. CHD5 has been shown to be a tumor suppressor gene candidate. This study investigated the involvement of CHD5 in ovarian cancer and its clinicopathological significance.
METHODS: CHD5 expression in ovarian cancer and its counterpart were determined by quantitative RT-PCR. The correlation of CHD5 expression to clinicopathological features of the tumor was analyzed.
RESULTS: CHD5 expression was downregulated by at least twofold in 32 of 72 (41%) invasive epithelial ovarian carcinomas when compared to 12 controls in Hong Kong Chinese women. CHD5 downregulation was correlated to clinical status (p < 0.05), but not to patient age, tumor type and grade, recurrence and clinical stage (p > 0.05). Survival analysis showed that patients with CHD5 downregulation in their tumors were associated with shorter disease-free and total survival times compared to those without CHD5 downregulation (p < 0.05). Cox proportional-hazards regression analysis indicated that downregulation of CHD5 is an independent adverse prognostic factor in ovarian cancer.
CONCLUSION: This study shows that CHD5 is downregulated in a certain number of ovarian cancers and appears to be an adverse predictor candidate of ovarian cancer disease-free and total survival.
Wang J, Chen H, Fu S, et al.The involvement of CHD5 hypermethylation in laryngeal squamous cell carcinoma.
Oral Oncol. 2011; 47(7):601-8 [PubMed
] Related Publications
Chromodomain helicase DNA-binding protein 5 (CHD5) has been found to be a candidate tumor suppressor gene (TSG) in malignant neural tumors. In mice heterozygous for chd5 deficiency, the first tumor observed was pathological squamous cell carcinoma. More than 95% of primary laryngeal cancer is squamous cell carcinoma. Thus, we explored the expression of CHD5 in 65 patients with laryngeal squamous cell carcinoma (LSCC) using real-time PCR, immunohistochemistry and Western blotting. DNA methylation was detected using bisulfate-specific sequencing. The potential function of CHD5 was determined using MTT, apoptosis and transwell migration assays in CHD5-transfected Hep-2 cells. Our results revealed that the mRNA and protein expression levels of CHD5 in LSCC tissues were significantly lower than those in clear surgical margin tissues (p<0.05), and there is a significant correlation between the mRNA and protein expression levels of CHD5 (p<0.01). In addition, there were significant differences in CHD5 mRNA and protein levels with respect to the patient's clinical stage (p<0.05). Aberrant methylation of the CHD5 promoter was frequently found in the Hep-2 cell line and LSCC tumor tissues, especially tumor tissues from advanced TNM (p<0.05) or older patients (p<0.05). Finally, ectopic expression of CHD5 in laryngeal cancer cells led to significant inhibition of growth and invasiveness. Our data suggest that CHD5 is a tumor suppressor gene that is epigenetically downregulated in LSCC.
Lang J, Tobias ES, Mackie RPreliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma.
Br J Dermatol. 2011; 164(5):1010-6 [PubMed
] Related Publications
BACKGROUND: Cutaneous melanoma is rapidly increasing in incidence worldwide and approximately 5% of melanomas are hereditary. Deletions in chromosome 1p36 have been detected in melanoma but no candidate melanoma tumour suppressor gene has yet been found in this area. Recently, strong evidence has been reported that CHD5 is a tumour suppressor gene in this region.
OBJECTIVES: To investigate CHD5 involvement in familial melanoma.
METHODS: Peripheral blood DNA from 47 melanoma families who do not carry mutations in any of the three currently recognized melanoma genes, 398 patients with sporadic melanoma and 398 geographically matched nonmelanoma-bearing controls were studied. Linkage investigation, single nucleotide polymorphism (SNP) genotyping and mutation screening studies were carried out on the CHD5 locus.
RESULTS: The CHD5 gene was not excluded by linkage analysis in any of the families. On SNP genotyping, the CHD5 rs7513548 SNP was found to be significantly associated with sporadic melanoma (odds ratio 1·53, 95% confidence interval 1·13-2·06). The AG genotype was found in 208 cases and 169 controls (cf. 141 and 175 cases and controls, respectively, for the AA genotype). On CHD5 mutation screening, a total of 50 single-base substitutions were detected. Of these, 39 were intronic and 11 were exonic. While 32 were previously recognized variants, 18 were newly identified. Three, in exons 4, 31 and 32, led to nonsynonymous substitutions. A p.Met1576Ile substitution was identified in a mother and daughter, both with invasive cutaneous melanoma.
CONCLUSIONS: This study appears to be the first report of CHD5 variants in familial cutaneous melanoma. Such CHD5 variants could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. As only one of the 47 families studied has this variant, it appears to be a rare event and further screening of melanoma families is required to confirm whether or not CHD5 is involved in melanoma pathogenesis.
Advanced prostate cancer can progress to systemic metastatic tumors, which are generally androgen insensitive and ultimately lethal. Here, we report a comprehensive genomic survey for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancer-related genes using next generation sequencing. Focal homozygous deletions were detected at 8p22, 10q23.31, 13q13.1, 13q14.11, and 13q14.12. Key genes mapping within these deleted regions include PTEN, BRCA2, C13ORF15, and SIAH3. Focal high-level amplifications were detected at 5p13.2-p12, 14q21.1, 7q22.1, and Xq12. Key amplified genes mapping within these regions include SKP2, FOXA1, and AR. Furthermore, targeted mutational analysis of normal-tumor pairs has identified somatic mutations in genes known to be associated with prostate cancer including AR and TP53, but has also revealed novel somatic point mutations in genes including MTOR, BRCA2, ARHGEF12, and CHD5. Finally, in one patient where multiple independent metastatic tumors were available, we show common and divergent somatic alterations that occur at both the copy number and point mutation level, supporting a model for a common clonal progenitor with metastatic tumor-specific divergence. Our study represents a deep genomic analysis of advanced metastatic prostate tumors and has revealed candidate somatic alterations, possibly contributing to lethal prostate cancer.
BACKGROUND: The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response.
RESULTS: We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival.
CONCLUSIONS: The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.
BACKGROUND: Nonhistone chromosomal proteins in concert with histones play important roles in the replication and repair of DNA and in the regulation of gene expression. The deregulation of these proteins can contribute to the development of a variety of diseases such as cancer. As a nonhistone chromosomal protein, chromodomain helicase DNA binding protein 5 (CHD5) has recently been identified as the product of a novel tumor suppressor gene (TSG), promoting the transcription of p19ink4a and p16arf. The inactivation of CHD5 was achieved partly through genetic deletion since it is located in 1p36, a region frequently deleted in human tumors. In this study, we aim to study the involvement of CHD5 in gastric cancer, the second most common cancer worldwide.
METHODS: CHD5 expression in a panel of gastric cancer cells were determined by quantitative RT-PCR. The methylation of CHD5 was evaluated by methylation specific PCR and bisulfite genome sequencing. The effect of CHD5 on growth of gastric cancer cells was tested by colony formation assay.
RESULTS: CHD5 expression was down-regulated in all of gastric cancer cell lines used (100%, 7/7) and significantly restored after pharmacological demethylation. Methylation of CHD5 promoter was detected in all of seven gastric cancer cell lines and in the majority of primary gastric carcinoma tissues examined (73%, 11/15). Finally, ectopic expression of CHD5 in gastric cancer cells led to a significant growth inhibition.
CONCLUSION: CHD5 was a TSG epigenetically down-regulated in gastric cancer.
BACKGROUND: Mutations and promoters' methylation of a set of candidate cancer genes (CAN genes) are associated with progression of colorectal cancer (CRC). We hypothesized that these genes' promoters are inactivated through epigenetic silencing and may show a different profile in high-risk populations. We investigated the status of CAN gene methylation and CHD5 protein expression in African American CRC tissue microarrays (TMA) using immunohistochemical staining.
METHODOLOGY/PRINCIPAL FINDINGS: The promoter methylation status of the CAN genes was studied by methylation-specific PCR (MSP) in 51 Iranians (a white population) and 51 African Americans (AA). Microsatellite instability (MSI) was analyzed as well. The differential frequency of methylation for each gene was tested by chi-square analysis between the two groups based on matched age and sex. CHD5 protein expression was evaluated in moderate to well differentiated and poorly differentiated carcinomas compared to matched normal tissue using TMA. In addition, the correlation between these epigenetic biomarkers and various clinicopathological factors, including, age, location, and stage of the disease were analyzed. Seventy-seven and 34% of tumors were distal in Iranian and African American patients, respectively. In both populations, the percentage of methylation was >65% for SYNE1, MMP2, APC2, GPNMB, EVL, PTPRD, and STARD8, whereas methylation was <50% for LGR6, RET, CD109, and RNF. The difference in methylation between the two populations was statistically significant for CHD5, ICAM5 and GPNMB. Thirty-one percent AA tumors showed MSI-H, compared to 28% in Iranians.
CONCLUSIONS/SIGNIFICANCE: A significantly higher methylation rate was found for GPNMB, ICAM5, and CHD5 genes in AA patients compared to Iranians. These genes might play a role in the high incidence and aggressiveness of CRC in the AA population. The hypermethylation of the CAN genes can be considered as a marker of colon carcinogenesis.
Chromodomain, helicase, DNA binding 5 (CHD5) is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a diverse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer samples by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 samples with normal CHD5 and in 2 of 3 samples with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 samples as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04). The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer; however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36.
Mulero-Navarro S, Esteller MChromatin remodeling factor CHD5 is silenced by promoter CpG island hypermethylation in human cancer.
Epigenetics. 2008 Jul-Aug; 3(4):210-5 [PubMed
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Changes in chromatin structure are an essential mechanism for gene regulation (transcription, replication, DNA repair and recombination). ATP-dependent chromatin-remodeling enzymes have previously been implicated in maintaining and regulating chromatin structure. These enzymes are divided into several groups including the SWI/SNF, ISWI and CHD families. Although the Chromodomain Helicase DNA-binding protein (CHD) family members are involved in key cellular processes, the disrupted regulation of their expression has not been fully assessed. An impairment of chromatin remodeling activity, mediated by promoter CpG island hypermethylation of the described candidate genes, could be key in cancer pathology. Herein, we examine the DNA methylation profiles of CHD family members (CHD1-9) in different tumor types. For all CHDs, CpG island hypermethylation was only observed at the CHD5 promoter in human cancer cell lines and primary tumors, particularly gliomas and colon and breast carcinomas. RT-qPCR analyses correlated CHD5 loss of expression with hypermethylation of the promoter, and restoration of CHD5 mRNA levels upon treatment with a DNA demethylating agent. These results underpin the epigenetic inactivation of the chromating remodeling factor CHD5 as one contributor for the aberrant structural changes of chromatin throughout the genome of the cancer cell.
Isidor B, Le Cunff M, Boceno M, et al.Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma.
Eur J Med Genet. 2008 Nov-Dec; 51(6):679-84 [PubMed
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Monosomy 1p36 is one of the most frequent subtelomeric microdeletion syndromes characterized by distinct craniofacial features and developmental delay/mental retardation. Other common symptoms include hypotonia, seizures, brain abnormalities, visual, auditory and heart defects. Neuroblastoma is a rare feature since to our knowledge only two patients with "pure" 1p36 deletion have been described. We report on a child with developmental delay and facial dysmorphy who developed neuroblastoma at 1 month of age. No primary site outside of the liver could be demonstrated and the tumour regressed spontaneously. Standard karyotyping was normal while subtelomeric screening using Multiplex Ligation-dependent Probe Amplification (MLPA) method revealed a constitutional de novo subtelomeric 1p36 deletion. Subsequent Agilent 244K oligonucleotide array-based comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis showed a complex 1p36.3 deletion/duplication rearrangement. Among the best candidate genes predisposing to the development of neuroblastoma located in 1p36, the AJAP1 gene is the only gene present in the duplication while CHD5, TNFRSF25 and CAMTA1 are located outside of the rearrangement. Therefore, a gene-dosage effect involving a gene located in the duplication including AJAP1 might explain the neuroblastoma observed in our patient. The rearrangement might equally interfere with the expression of a gene located outside of it (including CHD5 located 1Mb away from the rearrangement) playing a role in the tumorigenesis. In conclusion, this study illustrates the complexity of such rearrangement characterized by array CGH and strengthens that constitutional 1p36.3 rearrangement predisposes to the development of neuroblastoma.
BACKGROUND: Neuroblastomas are characterized by hemizygous 1p deletions, suggesting that a tumor suppressor gene resides in this region. We previously mapped the smallest region of consistent deletion to a 2-Mb region of 1p36.31 that encodes 23 genes. Based on mutation analysis, expression pattern, and putative function, we identified CHD5 as the best tumor suppressor gene candidate.
METHODS: We determined the methylation status of the CHD5 gene promoter in NLF and IMR5 (with 1p deletion) and SK-N-SH and SK-N-FI neuroblastoma cell lines using methylation-specific sequencing and measured CHD5 mRNA expression by reverse transcription polymerase chain reaction in cells treated with or without 5-aza-2-deoxycytidine, an inhibitor of DNA methylation. We transfected the cells with CHD5 and antisense (AS) CHD5 DNA to assess the effect of CHD5 overexpression and suppression, respectively, on colony formation in soft agar and growth of xenograft tumors in athymic mice. We also analyzed the association of CDH5 expression with outcomes of 99 neuroblastoma patients. Statistical tests were two-sided.
RESULTS: CHD5 expression was very low or absent in neuroblastoma cell lines. The CHD5 promoter was highly methylated in NLF and IMR5 lines, and CHD5 expression increased after treatment with 5-aza-2-deoxycytidine. Clonogenicity and tumor growth were abrogated in NLF and IMR5 cells overexpressing CHD5 compared with antisense CHD5 (clonogenicity: mean no. of colonies per plate, NLF-CHD5, 43 colonies, 95% confidence interval [CI] = 35 to 51 colonies, vs NLF-CHD5-AS, 74 colonies, 95% CI = 62 to 86 colonies, P < .001; IMR5-CHD5, 11 colonies, 95% CI = 2 to 20 colonies, vs IMR5-CHD5-AS, 39 colonies, 95% CI = 17 to 60 colonies, P = .01; tumor growth, n = 10 mice per group: mean tumor size at 5 weeks, NLF-CHD5, 0.36 cm(3), 95% CI = 0.17 to 0.44 cm(3), vs NLF-CHD5-AS, 1.65 cm(3), 95% CI = 0.83 to 2.46 cm(3), P = .002; IMR5-CHD5, 0.28 cm(3), 95% CI = 0.18 to 0.38 cm(3), vs IMR5-CHD5-AS, 1.15 cm(3), 95% CI = 0.43 to 1.87 cm(3); P = .01). High CHD5 expression was strongly associated with favorable event-free and overall survival (P < .001), even after correction for MYCN amplification and 1p deletion (P = .027).
CONCLUSIONS: CHD5 is the strongest candidate tumor suppressor gene that is deleted from 1p36.31 in neuroblastomas, and inactivation of the second allele may occur by an epigenetic mechanism.
Genomic analyses of late-stage human cancers have uncovered deletions encompassing 1p36, thereby providing an extensive body of literature supporting the idea that a potent tumor suppressor resides in this interval. Although several genes have been proposed as 1p36 candidate tumor suppressors, convincing evidence that their encoded products protect from cancer has been scanty. A recent functional study identified chromodomain helicase DNA-binding protein 5 (CHD5) as a novel tumor suppressor mapping to 1p36. Here, we discuss evidence supporting the tumor-suppressive role of CHD5. Together, these findings suggest that strategies designed to enhance CHD5 activity could provide novel approaches for treating a broad range of human malignancies.