Abstract B23: Crucial deubiquitinases in cancer cell survival

摘要: Deubiquitinases (DUBs) are enzymes that proteolytically cleave ubiquitin from substrates. Substrates include oncogenes, tumor suppressors and polyubiquitinated proteins marked for degradation by the proteasome. Ubiquitin specific peptidase-7 (USP7) deubiquitinates MDM2 (an oncogene). is a ligase ubiquitinates p53 (a suppressor protein), targeting it proteosomal degradation. As such, USP7 promising cancer target because its inhibition stabilizes thereby promotes apoptosis cell cycle arrest, processes often deregulated in tumors (Nicholson Suresh Kumar, 2011). We found was selectively druggable following fragment-based lead discovery effort to obtain antagonists. Cellular xenograft studies confirm inhibiting activity stabilized levels p53-downstream target, p21. Additionally, normal primary p53-null cells were less sensitive than corresponding p53-WT inhibition. To investigate whether other DUBs involved survival, we carried out drop-out CRISPR screen using pooled DUB library HCT116 A549 cells. Out of approximately 100 targeted, nine, including USP7, affect viability. These hits validated siRNA-mediated knockdown lines (A549, HCT116, MCF7). Three robustly decreased proliferation further tested (Human Mammary Epithelial Cells Human Bronchial Cells). protein expression also determined. In general, levels, efficiency higher compared Collectively, our support hypothesis may be an efficacious strategy promote death. Furthermore, there should considered as novel targets. Citation Format: Lorna Kategaya, Trinna Cuellar, Ben Haley, Jinfeng Liu, Andy Tran, Yi Cao, David Stokoe, Mark McCleland, Beth Blackwood, Sharon Yee, Joy Drobnick, Jake Drummond, James Ernst, Michael Kwok, Cuong Ly, Richard Pastor, Paola Di Lello, Chudi Ndubaku, Robert Blake, Vickie Tsui, Jeremy Murray, Till Maurer, Ingrid Wertz. Crucial deubiquitinases survival. [abstract]. In: Proceedings AACR Precision Medicine Series: Targeting Vulnerabilities Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B23.