Myc-stabilizing deubiquitinases (Myc-DUBs)

Myc-stabilizing deubiquitinases are a functional class of enzymes that regulate the stability and turnover of the Myc oncoprotein, a master regulator of cell proliferation and metabolism (Prieto et al., Cancers, 2021). Under normal physiological conditions, Myc is a highly unstable protein with a short half-life, targeted for degradation by the ubiquitin-proteasome system via E3 ligases such as FBW7 and SKP2 (Popov et al., Nature, 2007). Deubiquitinases (DUBs) like USP28, USP36, USP7, and USP22 counteract this process by removing ubiquitin chains from Myc, thereby preventing its degradation and maintaining high protein levels (Sun et al., EMBO Rep, 2015; Tavana et al., Sci Adv, 2016). In many cancers, these DUBs are overexpressed or dysregulated, leading to the pathological stabilization of Myc and driving uncontrolled tumor growth. Because Myc lacks a traditional small-molecule binding pocket, targeting the specific DUBs that stabilize Myc offers an indirect but effective therapeutic strategy to induce Myc degradation. Several small-molecule inhibitors targeting DUBs like USP7 and USP28 are currently under investigation for their ability to reduce Myc levels and inhibit tumor progression (Chauhan et al., Cancer Cell, 2012). However, a significant challenge remains in achieving high selectivity, as many DUBs have multiple cellular substrates beyond Myc, potentially leading to off-target toxicities.

Other names

Myc-stabilizing DUBsc-Myc deubiquitinating enzymesN-Myc stabilizing deubiquitinasesUSP28USP36USP7USP22

Inhibition of deubiquitinase activity prevents the removal of polyubiquitin chains from the Myc protein, which promotes its recognition and degradation by the 26S proteasome, thereby reducing Myc-mediated transcriptional activity (Prieto et al., Cancers, 2021).