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

Oncogene volume 43, pages 899–917 (2024)Cite this article

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Abstract

Dysregulation of MOF (also known as MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not catalytically inactive mutant (MOF-E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and deubiquitinates MOF at lysine 410, which protects it from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription in a JUN-dependent manner, which subsequently activates Wnt/β-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.

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Fig. 1: MOF protein is highly expressed in ESCC and predicts a worse prognosis.
Fig. 2: MOF plays an oncogenic role on ESCC growth and metastasis in vitro and in vivo.
Fig. 3: USP10 binds to and stabilizes MOF protein via deubiquitination.
Fig. 4: Dysregulation of USP10 in ESCC promotes tumor progression.
Fig. 5: MOF is essential for USP10-mediated tumor progression of ESCC.
Fig. 6: MOF activates ANXA2 transcription in a JUN-dependent manner.
Fig. 7: MOF promoted the proliferation, migration and invasion of ESCC cells via upregulating ANXA2.
Fig. 8: MOF accelerated ESCC cell proliferation, migration and invasion through activating Wnt signaling.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. RNA-Sequencing data produced in this study have been deposited in Gene Expression Omnibus (GEO) (GSE241066). Uncropped and full-length western blots are present in Supplementary Materials.

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Acknowledgements

We acknowledge Dr. Jian Zhu (Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China) for his valuable suggestions during the discussion of this project.

Funding

The project was financially supported by grants from the Special Construction Project Fund for Taishan Mountain Scholars of Shandong Province (to XZ), the Jinan Medicine Research Program (to XZ), and the National Natural Science Foundation of China (grants 32070712 to YZou).

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  1. These authors contributed equally: Peichao Li and Lingxiao Yang.

Authors and Affiliations

  1. Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China

    Peichao Li, Lingxiao Yang, Fanrong Liu, Yilin Zhu, Huacong Sui, Fengyuan Gao, Lingbing Li, Zhongxian Tian, Yunpeng Zhao & Xiaogang Zhao

  2. Key Laboratory of Chest Cancer, The Second Hospital, Shandong University, Jinan, Shandong, 250012, China

    Peichao Li, Zhongxian Tian & Xiaogang Zhao

  3. Division of Environmental Medicine, Department of Medicine, NYU Grossman School of Medicine, New York, 10010, USA

    Sun Young Park, Alex H. Li, Max Costa & Hong Sun

  4. Cancer Center, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China

    Lan Ye

  5. The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China

    Yongxin Zou

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Contributions

XZ, HSun, and PL conceived and designed this project. LYang performed most of the experiments. FL, YZhu, HSui, and FG helped with biochemistry experiments. LYe, YZhao, and LL helped with animal experiments and collected clinical samples. ZT and YZou provided the support of experimental techniques. PL, LYang, and SP analyzed all data and performed the visualization. LL made the mechanism diagram. PL, SP, AL, and HSun wrote the original draft. PL, SP, AL, HSun, MC, YZou, and XZ reviewed and edited the manuscript. XZ supervised all process of this study. All authors read and approved the final manuscript.

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Correspondence to Hong Sun or Xiaogang Zhao.

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This study was approved by the Ethics Committee of The Second Hospital of Shandong University (KYLL-2022P0233) and the Ethical Committee for Animal Experimentation of The Second Hospital of Shandong University (KYLL-2022A0233).

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Li, P., Yang, L., Park, S.Y. et al. Stabilization of MOF (KAT8) by USP10 promotes esophageal squamous cell carcinoma proliferation and metastasis through epigenetic activation of ANXA2/Wnt signaling. Oncogene 43, 899–917 (2024). https://doi.org/10.1038/s41388-024-02955-z

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