Stabilization of MOF (KAT8) by USP10 promotes esophageal squamous cell carcinoma proliferation and metastasis through epigenetic activation of ANXA2/Wnt signaling

Li, Peichao; Yang, Lingxiao; Park, Sun Young; Liu, Fanrong; Li, Alex H.; Zhu, Yilin; Sui, Huacong; Gao, Fengyuan; Li, Lingbing; Ye, Lan; Zou, Yongxin; Tian, Zhongxian; Zhao, Yunpeng; Costa, Max; Sun, Hong; Zhao, Xiaogang

doi:10.1038/s41388-024-02955-z

Cited by 4 publications

(1 citation statement)

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“…It has been reported that G3BP1 participates in the regulation of the Wnt/β-Catenin signaling pathway [ 33 – 35 ]. Interestingly, one recent study from our lab also demonstrated the important role of the abnormally activated Wnt signaling pathway in ESCC proliferation and metastasis [ 44 ]. Therefore, we continued to explore the effects of USP21 on Wnt/β-Catenin signaling and found that USP21 positively mediated the Wnt/β-Catenin pathway in a G3BP1-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling

Guo,

Zhao,

Sui

et al. 2024

Oncogenesis

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Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/β-Catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.

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Section: Discussionmentioning

confidence: 99%