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Deletions involving the chromosomal band 5q21 are among the most frequent alterations in prostate cancer. Using SNP arrays, we mapped a 1.3 megabase minimally deleted region including only the RGMB and CHD1 genes. Functional analyses demonstrated that CHD1 is an essential tumor suppressor. FISH analysis of 2,093 prostate cancers revealed a strong association between CHD1 deletion, 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 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 demonstrates a key role of this chromatin remodeling factor in prostate cancer biology.
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