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KEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation.

ABSTRACT: 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 (?K2) truncation or K249R mutation, leads to elevated protein stability. Furthermore, it is shown that the KEAP1/SOX9 interaction is modulated by CKI?-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.

SUBMITTER: Shao N

PROVIDER: S-EPMC7610265 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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KEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation.

Shao Na N Huang Hong H Idris Muhammad M Peng Xu X Xu Feng F Dong Shiwu S Liu Chungang C

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200927 21

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, ...[more]

PMID: 33173725

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Project description:BackgroundUbiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.MethodsImmunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression.ResultsUbe2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC.ConclusionsOur study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.

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KEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation.

Publications

KEAP1 Mutations Drive Tumorigenesis by Suppressing SOX9 Ubiquitination and Degradation.

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