The Role of CHD1 in DNA Rearrangements and Progression of Prostate Cancer

Abstract

Abstract : Most prostate cancers (PCa) are considered to be indolent (non-aggressive) and may not even require treatment. However, some of them are aggressive tumors that are characterized by DNA rearrangements resulting in cancer progression, recurrence and metastases, leading to 30,000 deaths in the U.S. annually. We hypothesize that the chromatin remodeler encoded by CHD1 affects the genesis and/or location of DNA rearrangement breakpoints which cause DNA copy number alterations (CNAs) at a number of genes, thereby playing a role in the development and progression of PCa. Specifically, we postulate that 1) loss of the CHD1 gene is associated with DNA rearrangements at particular locations in the tumor genome of PCa; 2) experimental knockout of Chd1 protein expression will lead to specific DNA copy number changes at genes that are concurrently altered with the CHD1 gene in PCa tumors; and 3) downregulation of CHD1 expression and its collaborative gene(s), including MAP3K7, will result in tumorigenesis and invasion of tumor cells. Using DNA of tumor and matched normal cells from multiple patient cohorts, genome-wide SNP arrays and the algorithm of Genomic Identification of Significant Targets in Cancer (GISTIC), we have identified and validated that 1) CHD1 is second only to PTEN as the most frequent homozygously deleted gene in PCa, and 2) tumors with loss of CHD1 represent a unique and distinct subtype of PCa. We further demonstrated that 1) complete loss of CHD1 is associated with a larger number of homozygous deletions (HODs) at other locations in the tumor genome, and 2) loss of CHD1 is associated with deletions on 2q22, 5q11.2 and 6q15 in the tumor genome. Together with the deletions observed in HEK293 cells stably transfected with CHD1 shRNA and dramatic morphological changes caused by down-regulation of Chd1 in mouse prostate epithelial cells, these data suggest a causal relationship, which warrants further investigation the role CHD1 in PCa progression.