Abstract 2742: USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity

Abstract

Abstract Dysregulation of the Ubiquitin proteasome system (UPS), which comprises nearly 1000 different components is associated with many aspects of oncogenesis and has emerged as a novel therapeutic target. We have previously shown that USP37 (Ubiquitin specific peptidase 37) antagonizes the tumor suppressor APCCDH1and it promotes S phase entry while data from other groups have shown that it stabilizes oncoproteins, such as c-Myc. We have found USP37 protein levels to be high in many cancerous cell lines as compared to untransformed cells and it appears to help tumor survive the high level of replication stress associated with oncogene expression. It was found that USP37 over expression confers survival advantage to cancer cells while its depletion enhances chemo sensitization in response to variety of replication stresses. USP37 over expressing cells were able to resolve γ-H2AX foci much more effectively then the wild type or cells in which USP37 was depleted. Our data indicate that USP37 binds and stabilizes the active form of CHK1 as evident by its protein levels when USP37 over expressing or depleted cells were exposed to replication stress. Mechanistically, our analyses indicate that USP37 stabilizes CHK1 by its deubiquitination, preventing its degradation. As CHK1 has been pursued as a therapeutic target with limited success our work defines a novel way to modulate activity of CHK1 while simultaneously targeting multiple oncogenes and thereby providing a rationale to evaluate USP37 inhibitor over CHK1 inhibitor as a potential therapeutic target in different cancers. Citation Format: mayank singh, Amy C. Burrows, Andrew Dickson, Matthew Summers. USP37 promote oncogenesis by stabilizing protein involved in DNA damage repair pathway and provides a novel way to modulate Chk1 activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2742.