title: Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
abstract: A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Lindberg
authors.forename: G
authors.initials: G
authors.lastname: Sui
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: L
authors.initials: L
authors.lastname: Egevad
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Xie
authors.forename: M
authors.initials: M
authors.lastname: Wan
authors.forename: S-T
authors.initials: ST
authors.lastname: Kim
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: A R
authors.initials: AR
authors.lastname: Turner
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Feng
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.forename: G S
authors.initials: GS
authors.lastname: Bova
authors.forename: C M
authors.initials: CM
authors.lastname: Ewing
authors.forename: G
authors.initials: G
authors.lastname: Yan
authors.forename: M
authors.initials: M
authors.lastname: Gielzak
authors.forename: S D
authors.initials: SD
authors.lastname: Cramer
authors.forename: R L
authors.initials: RL
authors.lastname: Vessella
authors.forename: S L
authors.initials: SL
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Grönberg
authors.forename: W B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: J
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D015536:Down-Regulation; D017353:Gene Deletion; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D004265:DNA Helicases; C080359:CHD1 protein, human