Project Details
Projekt
Targeting oncoprotein stability for cancer therapy
Subject Area
Hematology, Oncology
Biochemistry
Structural Biology
Cell Biology
Biochemistry
Structural Biology
Cell Biology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
The ubiquitin proteasome system controls the abundance of most cellular proteins. This system includes a set of enzymes, such as ubiquitin ligases and deubiquitinases, which transfer ubiquitin onto and remove it from protein substrates. Ubiquitinated substrates are degraded by a large proteolytic complex, the proteasome. Proteasome inhibition can be instrumental in suppressing cancer cell survival and has been successfully used in treatment of multiple myeloma. However, the mechanisms of cytotoxicity of proteasome inhibition remain elusive, highlighting the need for more selective therapies. Specific targeting of pathways, which maintain stability of oncoproteins may present an alternative antineoplastic strategy. Oncoproteins drive key biological processes during homeostasis, and often become indispensable for cell viability during tumorigenesis. The abundance of oncoproteins can be non-redundantly controlled by specific ubiquitin-dependent pathways, which include ubiquitin-specific proteases. For example, ablation of the Usp7 deubiquitinase in mouse germline destabilizes the oncogenic ubiquitin ligase Mdm2, hyperactivates p53, and leads to embryonic lethality, demonstrating that maintenance of oncoprotein stability is an essential cellular process. Ubiquitin-specific proteases are amenable to small molecule inhibition and therefore are promising therapeutic targets. Inhibitors of Usp7, which abrogate tumorigenesis in mice but are tolerated by healthy adult tissues, show that targeting oncoprotein stability creates a significant therapeutic window.A critical pathway, which controls degradation of multiple oncoproteins including Myc, Notch and cyclin E, is driven by the SCF(Fbw7) ubiquitin ligase. Fbw7 is essential for tissue homeostasis and its loss-of-function promotes tumorigenesis in mouse models. We have recently shown that Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. Depletion of Usp28 in tumor cell lines or genetic ablation of Usp28 in mice destabilizes Fbw7 substrates. Importantly, deletion of Usp28 in the intestine has only subtle effects on tissue homeostasis but strongly attenuates intestinal tumor development, and may thus provide a therapeutic window for solid tumors. Intriguingly, we find that loss of the catalytic activity of Usp28 is more efficient in promoting oncoprotein degradation than the complete gene knockout. Therefore, we speculate that inhibition of the catalytic function of Usp28 by small molecules might be particularly effective in tumor suppression. In this project, we will pursue the following aims: 1) model small molecule inhibition of Usp28 during homeostasis and tumorigenesis via expression of catalytically inactive Usp28 in mouse models, 2) elucidate the structural basis of deubiquitination by Usp28 and design small molecule inhibitors targeting Usp28, and 3) identify signaling events that promote oncoprotein degradation via the Usp28/Fbw7 pathway.
DFG Programme
Research Units
