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SUB1 promotes colorectal cancer metastasis by activating NF-κB signaling via UBR5-mediated ubiquitination of UBXN1

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Abstract

Metastasis accounts for the major cause of colorectal cancer (CRC) related mortality due to the lack of effective treatments. In this study, we integrated the single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog (Sac-Saccharomyces cerevisiae)/PC4 (positive cofactor 4) associated with CRC metastasis. Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC. In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells. SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis. Mechanistically, SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells. Subsequently, the increased UBR5 mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1, thus to activate the NF-κB signaling. Overall, our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling, providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.

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Data availability

All data included in this study are available from the public open-access databases or upon request by contact with the corresponding author Meng Xue (xuemeng@zju.edu.cn).

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Acknowledgement

This work was supported by the National Natural Science Foundation of China (82073229, 82072623).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China

    Hao Wang, Wenwen Chen, Yanting Wang, Shuyi Mi, Liangjing Wang & Meng Xue

  2. Institution of Gastroenterology, Zhejiang University, Hangzhou, 310058, China

    Hao Wang, Wenwen Chen, Yanting Wang, Shuyi Mi, Liangjing Wang & Meng Xue

  3. Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Yuzhen Gao

  4. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China

    Zizhen Zhang

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  1. Hao Wang
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  2. Wenwen Chen
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  3. Yanting Wang
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Correspondence to Liangjing Wang or Meng Xue.

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Wang, H., Chen, W., Wang, Y. et al. SUB1 promotes colorectal cancer metastasis by activating NF-κB signaling via UBR5-mediated ubiquitination of UBXN1. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2429-5

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