# DeSUMOylation regulation of c-Myc > **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $360,701 ## Abstract Project Summary While properly regulated levels of c-Myc are essential for normal cell growth and proliferation, aberrant overexpression and activation of c-Myc contribute to most human cancers. Thus, c-Myc level and activity must be tightly regulated during normal cell homeostasis. The rapid turnover of c-Myc is controlled by ubiquitin- dependent proteolysis. c-Myc can be ubiquitinated by the Threonine 58 phosphorylation-dependent ubiquitin ligase (E3) complex SCFFbw7 as well as various other ubiquitin E3s. Conversely, c-Myc ubiquitination can be reversed by the action of deubiquitinating enzymes (DUBs), including USP28, USP36 and USP37. Interestingly, c-Myc can also be modified by small ubiquitin-like modifiers (SUMOs). Yet the function of c-Myc SUMOylation is still unclear and how c-Myc is affected by deSUMOylation is unknown. We recently identified the SUMO protease SENP1 as a novel c-Myc deSUMOylating enzyme. SENP1 directly binds to and deSUMOylates c- Myc in cells and in vitro. Overexpression of wild-type (wt) SENP1, but not its catalytic-inactive mutant (C603S), stabilizes c-Myc and enhances c-Myc transactivation activity. Consistently, knockdown of SENP1 reduces c- Myc levels and suppresses cell proliferation. We further show that c-Myc can be co-modified by ubiquitin and SUMO and SENP1-mediated deSUMOylation reduces c-Myc ubiquitination, suggesting that SUMOylation promotes c-Myc degradation through the ubiquitin-proteasome system. In addition, SENP1 deSUMOylates USP28 whereas USP28 stabilizes SENP1 and Fbw7 reduces SENP1 levels. Thus, c-Myc levels and activity may be dynamically controlled by complex ubiquitination-SUMOylation crosstalk. SENP1 is frequently overexpressed, correlating with the high expression of c-Myc and poor patient survival, in human breast cancers. Together, these results lead to a novel hypothesis that SENP1 functions as a crucial regulator of c- Myc by deSUMOylating c-Myc. To gain further insight into the role of SENP1 in regulating c-Myc protein stability, activity and oncogenicity, we will investigate the molecular and biochemical mechanisms of the regulation of c-Myc by SENP1 in Aim 1, including how SENP1 contributes to c-Myc stabilization, how c-Myc is co-modified by SUMO and ubiquitin, and how it interplays with Fbw7 and USP28 to dynamically control c-Myc turnover. We will elucidate the role of SENP1 in c-Myc-mediated gene regulation in Aim 2 by analyzing whether SENP1 regulates c-Myc binding and turnover at target gene promoters, whether it regulates specific c- Myc target gene programs in response to growth signals, and whether SENP1 regulates the spatial localization of c-Myc in the nucleus. In Aim 3, we will test whether SENP1 potentiates c-Myc-driven transformation and mammary tumorigenesis, whether inhibiting SENP1 suppresses c-Myc-driven tumorigenesis in vivo, and whether SENP1 inhibition is efficacious in breast cancer. Achieving these goals will provide critical insight into how c-Myc is properly regu... ## Key facts - **NIH application ID:** 10843090 - **Project number:** 5R01CA186241-10 - **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY - **Principal Investigator:** Mu-Shui Dai - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $360,701 - **Award type:** 5 - **Project period:** 2015-04-01 → 2026-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10843090 ## Citation > US National Institutes of Health, RePORTER application 10843090, DeSUMOylation regulation of c-Myc (5R01CA186241-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10843090. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*