CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer

Burkhardt, Lia; Fuchs, Sarah; Krohn, Antje; Masser, Sawinee; Mader, Malte; Kluth, Martina; Bachmann, Frederik; Huland, Hartwig; Steuber, Thomas; Graefen, Markus; Schlomm, Thorsten; Minner, Sarah; Sauter, Guido; Sirma, Hüseyin; Simon, Ronald

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 ΒΌ 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 PPARg. 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.



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Burkhardt, Lia / Fuchs, Sarah / Krohn, Antje / et al: CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. 2013.


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