Title | CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Augello MA, Liu D, Deonarine LD, Robinson BD, Huang D, Stelloo S, Blattner M, Doane AS, Wong EWP, Chen Y, Rubin MA, Beltran H, Elemento O, Bergman AM, Zwart W, Sboner A, Dephoure N, Barbieri CE |
Journal | Cancer Cell |
Volume | 35 |
Issue | 4 |
Pagination | 603-617.e8 |
Date Published | 2019 04 15 |
ISSN | 1878-3686 |
Keywords | Animals, Carcinogenesis, Cell Line, Tumor, DNA Helicases, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Prostatic Neoplasms, Protein Binding, PTEN Phosphohydrolase, Receptors, Androgen, Signal Transduction, Tissue Culture Techniques, Transcription, Genetic, Tumor Suppressor Proteins |
Abstract | Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression. |
DOI | 10.1016/j.ccell.2019.03.001 |
Alternate Journal | Cancer Cell |
PubMed ID | 30930119 |
PubMed Central ID | PMC6467783 |
Grant List | K08 CA187417 / CA / NCI NIH HHS / United States P50 CA211024 / CA / NCI NIH HHS / United States R01 CA233650 / CA / NCI NIH HHS / United States R37 CA215040 / CA / NCI NIH HHS / United States |