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.

CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer

“…5B and 5C). Taken together, our findings are directly supported by 2 recent studies by Liu and colleagues and Huang and colleagues, who reported tumor suppressor properties of CHD1 while our study was under review (8,9).…”

“…The ability of clinical prostate cancers to survive and proliferate in the presence of 5q21 deletion may depend on the actual level of CHD1 downregulation, but suggests adaptive mechanisms that provide a selection advantage to CHD1-defective tumors particularly in cancers carrying homozygous deletions. This notion is consistent with the finding that CHD1-depleted prostate cancers harbor additional collaborative genetic alterations (8). An analogous situation has been reported for PTEN, where complete inactivation triggers a p53-dependent fail-safe response inducing growth arrest and senescence both in vitro and in vivo, and which is overcome by defective p53 pathway (29).…”

“…5-7). Two groups reported independently that CHD1 has tumor-suppressive features in prostate cancer (8,9). CHD1 is involved in assembly, shifting, and removal of nucleosomes from the DNA double helix to keep it in an open and transcriptionally active state (10).…”

“…The results of our study suggest that CHD1 is the tumor suppressor gene at 5q21 in prostate cancer. This notion is based on the localization of CHD1 within the smallest commonly deleted region (8,9) at 5q21, the association of the deletion with adverse features of prostate cancer, the link between 5q21 deletion and reduced expression of CHD1, and functional data showing a growth arrest in CHD1-overexpressing prostate cancer cells.…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…CHD1 was identified as frequently deleted in the homozygous form in prostate cancer [84] and likely contributes to cellular invasiveness [85]. CHD4/Mi-2b has been found to be deleted in a high percentage (17%) of endometrial cancers and is implicated as an autoantigen in the inflammatory disorder dermatomyositis [86].…”