Abstract 4140: Non-proteolytic regulation of oncogenic transcription factors by deubiquitinases

Abstract Oncogenic transcription factors (TFs) such as ETS2 and TEAD4 are critical regulators of genes driving cancer progression, including those involved in proliferation, survival, and metastasis. Despite their importance, the mechanisms modulating their activity through ubiquitination remain poorly understood. This study investigates deubiquitinases (DUBs) that interact with and regulate ETS2 and TEAD4, aiming to uncover novel insights into their transcriptional control.A DUB sub-library screening identified USP39 and OTUD6A as regulators of ETS2 and TEAD4, respectively. USP39 interacts with ETS2 via their amino-terminal regions, independent of the zinc finger and PNT domains, and deubiquitinates ETS2. This interaction reduces ETS2’s nuclear localization and transcriptional activity without affecting its stability, indicating a negative regulatory role. In contrast, OTUD6A interacts with TEAD4 at its YAP-binding domain and deubiquitinates TEAD4. OTUD6A further enhances TEAD4 transcriptional activity and cofactor interactions, notably by promoting YAP binding. Similar to USP39 and ETS2, OTUD6A does not influence TEAD4 stability but positively regulates its activity.These findings highlight the distinct, non-proteolytic roles of USP39 and OTUD6A in modulating transcriptional activity of ETS2 and TEAD4, respectively. Our findings underscore the functional diversity and opposing regulatory mechanisms of DUBs in oncogenic transcriptional control. Citation Format: Yunsik Choi. Non-proteolytic regulation of oncogenic transcription factors by deubiquitinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4140.