Dataset Information

Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer.

ABSTRACT: Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables. CHD8 expression was decreased in HGPIN, localized, and metastatic PCa compared to benign (P < .001). CHD8 promoter hypermethylation, assessed by Quantitative Pyrosequencing, occurred in over 45% of primary cancers in this population as well as the TGCA database. Treatment of cell lines with the demethylating agent 5-Aza-2'-deoxycytidine reinduced expression. An interesting dichotomy for CHD8 was observed within primary cancers, with higher nuclear protein expression associated with adverse clinical outcomes including extracapsular extension (P = .007), presence of metastases (P = .025) and worse PSA-recurrence free survival (P = .048). CHD8 outperformed Gleason score and predicted biochemical failure within intermediate grade prostate cancers. The BORIS/CTCF expression ratio increased in localized (P = .03) and metastatic PCa (P = .006) and was associated with higher Gleason score (P = .02), increased tumor volume (P = .02) and positive margins (P = .04). Per cell heterogeneity of expression revealed all protein expression to be more heterogeneous in cancerous tissue (both P < .001), especially high grade (P < .01). In the first detailed analysis in cancer, a marked loss of CHD8 expression and increased BORIS/CTCF ratio indicate frequent disruption of CTCF and its effector genes in PCa.

SUBMITTER: Damaschke NA

PROVIDER: S-EPMC4309256 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer.

Damaschke Nathan A NA Yang Bing B Blute Michael L ML Lin Chee Paul CP Huang Wei W Jarrard David F DF

Neoplasia (New York, N.Y.) 20141201 12

Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared agains ...[more]

PMID: 25499215

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Project description:Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4-the core component of the nucleosome remodeling and deacetylase (NuRD) complex-may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either 'deleterious', 'probably/possibly damaging' or as 'high/medium pathogenic'; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

Dataset Information

Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer.

Publications

Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer.

Similar Datasets

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