Open AccessKEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation
Author(s) -
Shao Na,
Huang Hong,
Idris Muhammad,
Peng Xu,
Xu Feng,
Dong Shiwu,
Liu Chungang
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202001018
Subject(s) - ubiquitin , ubiquitin ligase , carcinogenesis , proteasome , microbiology and biotechnology , keap1 , mutation , biology , dna damage , phosphorylation , chemistry , transcription factor , cancer research , genetics , dna , gene
The transcription factor SOX9 is frequently amplified in diverse advanced‐stage human tumors. Its stability has been shown to be tightly controlled by ubiquitination‐dependent proteasome degradation. However, the exact underlying molecular mechanisms remain unclear. This work reports that SOX9 protein abundance is regulated by the Cullin 3‐based ubiquitin ligase KEAP1 via proteasome‐mediated degradation. Loss‐of‐function mutations in KEAP1 compromise polyubiquitination‐mediated SOX9 degradation, leading to increased protein levels, which facilitate tumorigenesis. Moreover, the loss of critical ubiquitination residues in SOX9, by either a SOX9 (ΔK2) truncation or K249R mutation, leads to elevated protein stability. Furthermore, it is shown that the KEAP1/SOX9 interaction is modulated by CKI γ ‐mediated phosphorylation. Importantly, it is demonstrated that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the KEAP1/SOX9 interaction and its consequent degradation. Collectively, herein the findings uncover a novel molecular mechanism through which SOX9 protein stability is negatively regulated by KEAP1 to control tumorigenesis. Thus, these results suggest that mitigating SOX9 resistance to KEAP1‐mediated degradation can represent a novel therapeutic strategy for cancers with KEAP1 mutations.