CHD5, a tumor suppressor that is epigenetically silenced in lung cancer

Zhao, Rui; Yan, Qin; Lv, Jingye; Huang, Haili; Wen-ling, Zheng; Bao, Zhenmin; Ma, Wenxue

doi:10.1016/j.lungcan.2011.11.019

Cited by 50 publications

(56 citation statements)

References 21 publications

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“…Instead, the promoter of the remaining allele is frequently methylated, resulting in epigenetic silencing [9,14] and transcription could be silenced by other mechanisms, such as histone modification. Therefore, reversing the epigenetic modifications that result in transcriptional silencing of CHD5 [19– 23] should restore expression of an intact allele and presumably restore growth control. Thus, it will be important to identify the genes and proteins that regulate CHD5 expression, the genes that CHD5 regulates and the proteins with which CHD5 interacts, to fully understand the role of CHD5 in normal development as well as malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex

Kolla

Naraparaju

Zhuang

et al. 2015

Biochemical Journal

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Eukaryotic gene expression is developmentally regulated, in part by chromatin remodelling, and its dysregulation has been linked to cancer. CHD5 (chromodomain helicase DNA-binding protein 5) is a tumour suppressor gene (TSG) that maps to a region of consistent deletion on 1p36.31 in neuroblastomas (NBs) and other tumour types. CHD5 encodes a protein with chromatin remodelling, helicase and DNA-binding motifs that is preferentially expressed in neural and testicular tissues. CHD5 is highly homologous to CHD3 and CHD4, which are the core subunits of nucleosome remodelling and deacetylation (NuRD) complexes. To determine if CHD5 forms a similar complex, we performed studies on nuclear extracts from NBLS, SY5Y (both with endogenous CHD5 expression), NLF (CHD5 null) and NLF cells stably transfected with CHD5 cDNA (wild-type and V5–histidine-tagged). Immunoprecipitation (IP) was performed with either CHD5 antibody or antibody to V5/histidine-tagged protein. We identified NuRD components both by GST–FOG1 (Friend Of GATA1) pull-down and by IP. We also performed MS/MS analysis to confirm the presence of CHD5 or other protein components of the NuRD complex, as well as to identify other novel proteins. CHD5 was clearly associated with all canonical NuRD components, including metastasis-associated protein (MTA)1/2, GATA zinc finger domain containing 2A (GATAD2A), histone deacetylase (HDAC)1/2, retinoblastoma-binding protein (RBBP)4/7 and methyl DNA-binding domain protein (MBD)2/3, as determined by Western blotting and MS/MS. Our data suggest CHD5 forms a NuRD complex similar to CHD4. However, CHD5–NuRD may also have unique protein associations that confer functional specificity and may contribute to normal development and to tumour suppression in NB and other cancers.

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Section: Discussionmentioning

confidence: 99%

The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex

Kolla

Naraparaju

Zhuang

et al. 2015

Biochemical Journal

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“…Furthermore, it also has been reported that aberrant CHD5 promoter methylation was detected in gastric, colorectal, ovarian and lung cancer (20)(21)(22)(23). However, to the best of our knowledge, the role of CHD5 promoter methylation status in breast cancer has not been evaluated.…”

Section: Discussionmentioning

confidence: 94%

Decreased expression of the CHD5 gene and its clinicopathological significance in breast cancer: Correlation with aberrant DNA methylation

Song

Liu

Han³

et al. 2016

Oncology Letters

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Abstract. Chromodomain helicase DNA binding protein 5 (CHD5) has been identified as a tumor suppressor in mouse models. Downregulation of CHD5 gene expression is frequently observed in breast cancer cells and tissues. This may be explained by deletions or other mutations; however, alternative mechanisms require investigation. Therefore, the present study evaluated whether CHD5 aberrant methylation has a role in primary breast tumors. A total of 389 patients with primary breast cancer (including 252 paraffin-embedded specimens and 137 fresh-frozen samples) were enrolled in the present study. In the current study, reverse transcription-polymerase chain reaction (RT-PCR) and nested-methylation-specific PCR were used to analyze the mRNA expression and promoter methylation of CHD5 genes in a large cohort of breast cancer patients, and to investigate their associations with the clinicopathological features of tumors. CHD5 expression was significantly suppressed in breast cancer tissues compared with normal breast tissues when analyzed by RT-PCR. Furthermore, DNA methylation of CHD5 was more prevalent in breast tumors than in normal tissues. CHD5 mRNA levels correlated with the degree of CHD5 methylation in breast cancer tissues. Clinicopathological correlation analysis revealed that CHD5 promoter methylation was associated with estrogen receptor and progesterone receptor status. Thus, downregulation of CHD5, mediated by abnormal methylation, may contribute to the development and progression of breast cancer.

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“…Further, CHD5 can be reexpressed by exposure to the demethylating agent 5-aza-2′-deoxycytidine [73]. Finally, CHD5 is apparently involved in a variety of other cancer types, thus suggesting that it is an important TSG [76-82]. Thus, CHD5 is a bona fide TSG in NBs, but the remaining allele is transcriptionally silenced by an epigenetic mechanism, rather than mutation.…”

Section: Genes Inactivated By Deletion Mutation or Epigenetic Silmentioning

confidence: 99%

Therapeutic targets for neuroblastomas

Brodeur

Iyer

Croucher

et al. 2014

Expert Opinion on Therapeutic Targets

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Introduction Neuroblastoma (NB) is the most common and deadly solid tumor in children. Despite recent improvements, the long-term outlook for high-risk NB is still < 50%. Further, there is considerable short- and long-term toxicity. More effective, less toxic therapy is needed, and the development of targeted therapies offers great promise. Areas covered Relevant literature was reviewed to identify current and future therapeutic targets that are critical to malignant transformation and progression of NB. The potential or actual NB therapeutic targets are classified into four categories: i) genes activated by amplification, mutation, translocation or autocrine overexpression; ii) genes inactivated by deletion, mutation or epigenetic silencing; iii) membrane-associated genes expressed on most NBs but few other tissues; or iv) common target genes relevant to NB as well as other tumors. Expert opinion Therapeutic approaches have been developed to some of these targets, but many remain untargeted at the present time. It is unlikely that single targeted agents will be sufficient for long-term cure, at least for high-risk NBs. The challenge will be how to integrate targeted agents with each other and with conventional therapy to enhance their efficacy, while simultaneously reducing systemic toxicity.

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CHD5, a tumor suppressor that is epigenetically silenced in lung cancer

Cited by 50 publications

References 21 publications

The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex

The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex

Decreased expression of the CHD5 gene and its clinicopathological significance in breast cancer: Correlation with aberrant DNA methylation

Therapeutic targets for neuroblastomas

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