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.
Oncogene. 2023 Apr 24 [Epub]
Zhiping Li, Xuanmao Jiao, A Gordon Robertson, Gabriele Di Sante, Anthony W Ashton, Agnese DiRocco, Min Wang, Jun Zhao, Sankar Addya, Chenguang Wang, Peter A McCue, Andrew P South, Carlos Cordon-Cardo, Runzhi Liu, Kishan Patel, Rasha Hamid, Jorim Parmar, James B DuHadaway, Steven J M Jones, Mathew C Casimiro, Nikolaus Schultz, Andrew Kossenkov, Lai Yee Phoon, Hao Chen, Li Lan, Yunguang Sun, Kenneth A Iczkowski, Hallgeir Rui, Richard G Pestell
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA., Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, VSZ 4S6, Canada., Department of Cancer Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA., Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA., Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Bluemle Life Sciences Building, 233 South 10th Street, Philadelphia, PA, 19107, USA., Department of Pathology, Mt. Sinai, Hospital, 1468 Madison Ave., Floor 15, New York, NY, 10029, USA., Lankenau Institute for Medical Research, 100 East Lancaster Avenue, Wynnewood, PA, 19096, USA., Human Oncology and Pathogenesis Program, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Center for Systems and Computational Biology, The Wistar Institute, 3601 Spruce St., Philadelphia, PA, 19104, USA., Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA., Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA., Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902, USA. .