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GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma

Oncogene (2024)Cite this article

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Abstract

Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

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Fig. 1: GOLM1 is upregulated in Lenvatinib resistant HCC.
Fig. 2: GOLM1 upregulation promotes Lenvatinib resistance in vitro.
Fig. 3: GOLM1 overexpression induced Lenvatinib resistance in vivo.
Fig. 4: GOLM1 binds CSN5 and positively regulates CSN5 expression.
Fig. 5: GOLM1 binds CSN5 and positively regulates CSN5 expression.
Fig. 6: CSN5 stabilizes GOLM1 through deubiquitylation.
Fig. 7: GOLM1 knockdown in synergy with Lenvatinib treatment in vivo and GOLM1-EGFR-STAT3-CSN5 axis is coactivated in human HCC samples.

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Data availability

The data used to support the findings of this study are included and available within the article. The RNA-seq data has been uploaded to GEO database (Accession number: GSE273819).

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Funding

This work was funded by National Natural Science Foundation of China (82172739, 82102959), Natural Science Foundation of Shanghai (21ZR1481900), Zhongshan talent development program (2021ZSYQ11).

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Author notes

  1. These authors contributed equally: Peiyi Xie, Mengyuan Wu, Hui Wang, Bo Zhang, Zihao Zhang.

Authors and Affiliations

  1. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China

    Peiyi Xie, Bo Zhang, Mincheng Yu, Qiang Yu, Yufei Zhao, Min Xu, Wenxin Xu, Hui Li, Yongfeng Xu, Yongsheng Xiao & Lei Guo

  2. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China

    Mengyuan Wu

  3. Department of Molecular Biology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, PR China

    Hui Wang

  4. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China

    Zihao Zhang

  5. Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China

    Jiuliang Yan

  6. Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, PR China

    Da Huang

  7. Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Translational Research Center, Shanghai, 200031, PR China

    Hui Li

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Contributions

PX, MW, HW, BZ, ZZ and JY designed and performed experiments, analyzed data, and wrote the manuscript. MY, QY, YZ, DH, MX and WX analyzed data. YX, YX and HL provided patient tissue samples and analyzed clinical data. LG, YX, YX and HL supervised the entire project, obtained funding, designed the experiments and revised the manuscript.

Corresponding authors

Correspondence to Hui Li, Yongfeng Xu, Yongsheng Xiao or Lei Guo.

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All methods were performed in accordance with the relevant guidelines and regulations. All study participants provided informed consent, and the study design was approved by Research Ethics Committee of Zhongshan Hospital (approval number: B2021-464). Informed consent was obtained from all participants. Written informed consent for publication of the images from human research participants have been obtained.

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Xie, P., Wu, M., Wang, H. et al. GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma. Oncogene (2024). https://doi.org/10.1038/s41388-024-03153-7

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