The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFb activity and DNA damage. Reduced increased DNA damage in response to genotoxic stresses. was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFb kinase inhibitors. Reduced expression may define a subclass of PCa that warrants specific therapies.