USP21 functions as an oncogenic regulator of the Mdm2-p53 axis in colorectal cancer

The tumor suppressor p53 is a pivotal guardian against tumorigenesis, with its activity primarily constrained by the ubiquitin E3 ligase Mdm2. However, the full complexity of the Mdm2-p53 regulatory network remains elusive. Here we report that the deubiquitinating enzyme USP21 physically interacts with and stabilizes Mdm2 in a deubiquitinase activity-independent manner. Mechanistically, USP21 acts as a scaffold to facilitate the USP7-Mdm2 interaction, enhancing Mdm2 stability and consequently promoting p53 ubiquitination and degradation. Functionally, USP21-mediated p53 suppression attenuates its tumor suppressive activity and accelerates colorectal cancer progression. Clinically, USP21 is upregulated in colorectal cancer tissues, and its elevated expression correlates with poor overall survival in patients with wild-type p53 tumors, but not in those with p53 mutations. These findings establish USP21 as an important regulator of the Mdm2-p53 axis and reveal its critical role in promoting colorectal carcinogenesis via p53 inhibition.