title: 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.
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Damaschke
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Blute
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Chee Paul
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI; Environmental and Molecular Toxicology, University of Wisconsin, Madison, WI. Electronic address: jarrard@urology.wisc.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
mesh_terms: D000076246:CCCTC-Binding Factor; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D000076246:CCCTC-Binding Factor; C523331:CHD8 protein, human; C000619697:CTCF protein, human; C456540:CTCFL protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors