CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Augello, Michael A; Liu, Deli; Deonarine, Lesa D; Robinson, Brian D; Huang, Dennis; Stelloo, Suzan; Blattner, Mirjam; Doane, Ashley S; Wong, Elissa W P; Chen, Yu; Rubin, Mark A.; Beltran, Himisha; Elemento, Olivier; Bergman, Andries M; Zwart, Wilbert; Sboner, Andrea; Dephoure, Noah; Barbieri, Christopher E (2019). CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis. Cancer cell, 35(4), 603-617.e8. Cell Press 10.1016/j.ccell.2019.03.001

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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.

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