GSE123333
CHD1 functions as a prostate-specific tumor suppressor by modulating nuclear receptor specificity towards distinct, lineage-specific, enhancers
Deregulation of chromatin architecture is emerging as a critical feature of carcinogenesis, and genomic alterations in nucleosome remodelers are common in human cancer. Recurrent deletion of the chromatin remodeler CHD1 is among the most common alterations in prostate cancer, but its role as a tumor suppressor and the reasons for the tissue-specific nature of CHD1 deletion remain undefined. Here, we show that deletion of CHD1 drives prostate tumorigenesis and fundamentally reprograms the transcriptional program of the androgen receptor (AR), diverting AR towards an oncogenic transcriptional program and away from a growth suppressive transcriptome.  Conditional deletion of Chd1 in mouse prostate resulted in prostate neoplasia in vivo, confirming CHD1 as a tumor suppressor in prostate tissue. In prostate cells, the interactome of chromatin-bound CHD1 was enriched for factors that regulate nuclear receptor function, and interrogation of the CHD1 cistrome revealed promoter-independent enrichment of CHD1 at sites specifically occupied by AR and its associated transcriptional regulators. Deletion of CHD1 resulted in a dramatic redistribution of AR across the genome, localizing AR to sites enriched for HOXB13, and depleting AR at AR-halfsite motifs, consistent with the AR cistrome and epigenetic marks in human prostate cancer samples. Furthermore, the CHD1 null AR cistrome was associated with a unique AR transcriptional signature, enriched for pro-oncogenic pathways and depleted for processes consistent with normal prostatic function. Collectively, these data implicate CHD1 as a prostate-specific tumor suppressor which constrains the oncogenic functions of AR though maintenance of a normal AR transcriptional program. Overall design: LNCaP isogenic models of CHD1 loss cells were initally assessed for chromatin acessibility via ATAC seq. Briefly, Cells were starved of androgen for 72 hours, and the treated with either Vehicle (EtOH) or 10nM DHT for 4 hours.  Cells were then fixed with 4% PFA, and ATAC libraries and sequencing performed by the Center for Functional Cancer Epigenetics at Dana Farber research institute.  Samples were submitted in biological duplicate.