Li Zhiping, Jiao Xuanmao, Robertson A Gordon, Sante Gabriele Di, Ashton Anthony W, DiRocco Agnese, Wang Min, Zhao Jun, Addya Sankar, Wang Chenguang, McCue Peter A, South Andrew P, Cordon-Cardo Carlos, Liu Runzhi, Patel Kishan, Hamid Rasha, Parmar Jorim, DuHadaway James B, Jones Steven J, Casimiro Mathew C, Schultz Nikolaus, Kossenkov Andrew, Phoon Lai Yee, Chen Hao, Lan Li, Sun Yunguang, Iczkowski Kenneth A, Rui Hallgeir, Pestell Richard G
Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA, 18902 Pennsylvania.
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
Res Sq. 2023 Jan 10:rs.3.rs-2423179. doi: 10.21203/rs.3.rs-2423179/v1.
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.
前列腺癌（PCa）是美国男性第二大死因，包括具有不同治疗易感性的不同基因亚型。该基因编码一种翼状螺旋/叉头DNA结合蛋白，可竞争与FOXM1位点的结合。在此，13q21.31-q21.33区域内的该基因缺失在高达18%的人类PCa中出现，并与AR活性增加和预后不良相关。在前列腺癌基因工程小鼠中，该基因的前列腺特异性缺失增强了前列腺上皮内瘤变（PIN），并与TGFb活性增加和DNA损伤相关。该基因减少会增加对基因毒性应激的DNA损伤。该基因被招募到DNA损伤位点，增强了Ku70/Ku80的招募。该基因表达降低与同源定向修复增加以及对PARP抑制剂和TGFb激酶抑制剂的抗性相关。该基因表达降低可能定义了一类需要特定治疗的PCa亚类。
