OTUD7B is a new deubiquitinase targeting p53

作者：Chaopu Ding, Leixi Cao, Ruijie Wang, Qiong Wu, Mengfan Li, Jinjing Zhang, Rick F. Thorne, Jinming Li, Jianli Ma, Mian Wu, Shundong Cang · 发表于：Theranostics · 年份：2025 · DOI：10.7150/thno.103012 · 被引用次数：11 · 研究领域：Ubiquitin and proteasome pathways、Cancer-related Molecular Pathways、Cancer Research and Treatments

Rationale:The tumor suppressor p53 safeguards against cellular transformation, with its expression regulated by diverse post-translational modifications (PTMs).While polyubiquitination by Mdm2 principally drives its proteasomal degradation, the identity of p53 deubiquitinases (DUBs) remains less well defined.This study investigates the role of the deubiquitinase enzyme OTUD7B in hepatocellular carcinoma (HCC), where it is notably downregulated and proposed to function as a tumor suppressor.Methods: Mass spectrometry screening of immunoprecipitates from HCC cells was used to identify OTUD7B-binding proteins.Co-immunoprecipitation assays with endogenous, ectopic, and mutant forms of OTUD7B and p53 assessed binding interactions and p53 polyubiquitination levels, respectively.Regulatory mechanisms were explored via luciferase reporter and chromatin immunoprecipitation (ChIP) assays.OTUD7B function was evaluated in vitro and in xenograft models using shRNA knockdown, overexpression, and CRISPR-Cas9 knockout.OTUD7B expression in normal and HCC tissues was analyzed by immunohistochemistry and immunoblotting.Results: We identified p53 as a binding partner of OTUD7B, confirming interactions with both wild-type and mutant p53 in HCC cells.OTUD7B was shown to remove lysine-linked polyubiquitin chains in p53, including those mediated by Mdm2, thereby stabilizing p53 by inhibiting its proteasomal degradation.Overexpression of OTUD7B suppressed growth in HCC cultures and xenografts through...