title: CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer.
abstract: Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostate cancer. Using single-nucleotide polymorphism (SNP) arrays, we mapped a 1.3 megabase minimally deleted region including only the repulsive guidance molecule B (RGMB) and chromodomain helicase DNA-binding protein 1 (CHD1) genes. Functional analyses showed that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, prostate-specific antigen (PSA) biochemical failure (P = 0.0038), and absence of ERG fusion (P < 0.0001). We found that inactivation of CHD1 in vitro prevents formation of ERG rearrangements due to impairment of androgen receptor (AR)-dependent transcription, a prerequisite for ERG translocation. CHD1 is required for efficient recruitment of AR to responsive promoters and regulates expression of known AR-responsive tumor suppressor genes, including NKX3-1, FOXO1, and PPARγ. Our study establishes CHD1 as the 5q21 tumor suppressor gene in prostate cancer and shows a key role of this chromatin remodeling factor in prostate cancer biology.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Burkhardt
authors.forename: Sarah
authors.initials: S
authors.lastname: Fuchs
authors.forename: Antje
authors.initials: A
authors.lastname: Krohn
authors.forename: Sawinee
authors.initials: S
authors.lastname: Masser
authors.forename: Malte
authors.initials: M
authors.lastname: Mader
authors.forename: Martina
authors.initials: M
authors.lastname: Kluth
authors.forename: Frederik
authors.initials: F
authors.lastname: Bachmann
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.forename: Thomas
authors.initials: T
authors.lastname: Steuber
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sirma
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
mesh_terms: D045744:Cell Line, Tumor; D002895:Chromosomes, Human, Pair 5; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017430:Prostate-Specific Antigen; D004265:DNA Helicases; C080359:CHD1 protein, human