The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses. Oncogene 2023 Jun;42(22):1857-1873
Date
04/25/2023Pubmed ID
37095257Pubmed Central ID
PMC10238272DOI
10.1038/s41388-023-02668-9Scopus ID
2-s2.0-85153365483 (requires institutional sign-in at Scopus site)Abstract
Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 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 Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.
Author List
Li Z, Jiao X, Robertson AG, Di Sante G, Ashton AW, DiRocco A, Wang M, Zhao J, Addya S, Wang C, McCue PA, South AP, Cordon-Cardo C, Liu R, Patel K, Hamid R, Parmar J, DuHadaway JB, Jones SJM, Casimiro MC, Schultz N, Kossenkov A, Phoon LY, Chen H, Lan L, Sun Y, Iczkowski KA, Rui H, Pestell RGAuthor
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
DNA DamageEye Proteins
Humans
Male
Prostate
Prostatic Intraepithelial Neoplasia
Prostatic Neoplasms
Transcription Factors
Transforming Growth Factor beta
