Altered Androgen Receptor Activity Drives CHD1-Null Prostate Cancer

CHD1 is a ubiquitously expressed ATP-dependent chromatin remodeling enzyme that is required for efficient transcription, differentiation, and growth. Genomic profiling efforts have established CHD1 as a prostate-specific tumor suppressor, but the basis of its lineage-restricted effects on neoplastic growth remain unclear. To define the prostate-specific effects of CHD1 loss, Augello and colleagues generated a genetic mouse model harboring the targeted deletion of Chd1 in mouse prostate epithelial tissue. Extensive characterization showed that although Chd1 loss alone could not initiate tumor formation, Chd1-null prostate epithelium showed increased proliferation during androgen-driven regrowth after castration, suggesting that CHD1 could exert its tumorigenic effects in part via androgen receptor (AR) activity. Chromatin immunoprecipitation sequencing profiling of the CHD1 cistrome in the AR-positive human prostate cancer cell line LNCaP revealed that CHD1 binding was preserved at promoters of actively transcribed genes, indicating that CHD1 exerts its tumor-suppressive effects independently of its canonical promoter-specific function. Proteomic characterization of the chromatin-bound peptide interactome of CHD1 and AR showed that AR shared almost half of its chromatin-bound cofactors with CHD1. Further, detailed annotation of the CHD1 and H3K4me3 cistromes in prostate cancer models revealed that CHD1 colocalizes to AR-associated enhancer regions. CRISPR-mediated ablation of CHD1 in LNCaP cells resulted in resistance to the growth-inhibitory effects of high-dose androgen exposure, AR enrichment at HOXB13 sites, and more than 20,000 differentially bound AR peaks on chromatin in the absence of CHD1, collectively suggesting that CHD1 maintains a chromatin state that is required for normal AR function, whereas loss of CHD1 promotes oncogenic AR-driven transcription. Transcriptomic analysis of CHD1-deficient human cell lines and prostate organoids identified a unique AR-dependent transcriptome in CHD1-deficient prostate tumors. Together, this study provides further evidence that CHD1 is a tumor suppressor in prostate cancer and describes how CHD1-directed chromatin state changes drive AR-dependent transcriptional rewiring in prostate tumorigenesis.

Augello MA, Liu D, Deonarine LD, Robinson BD, Huang D, Stelloo S, et al. CHD1 loss alters AR binding at lineage-specific enhancers and modulates distinct transcriptional programs to drive prostate tumorigenesis. Cancer Cell 2019 Mar 28 [Epub ahead of print].

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