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TRIM69 suppressed the anoikis resistance and metastasis of gastric cancer through ubiquitin‒proteasome-mediated degradation of PRKCD

Oncogene volume 42, pages 3619–3632 (2023)Cite this article

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Abstract

The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis resistance and metastasis of GC cells remains to be elucidated. We identified the differentially expressed genes in anoikis-resistant GC cells using RNA-sequencing analysis. The interaction between TRIM69 and PRKCD was analyzed by coimmunoprecipitation and mass spectrometry. Our results have shown that TRIM69 was significantly downregulated in anoikis-resistant GC cells. TRIM69 overexpression markedly suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo. TRIM69 knockdown had the opposite effects. Mechanistically, TRIM69 interacted with PRKCD through its B-box domain and catalyzed the K48-linked polyubiquitination of PRKCD. Moreover, TRIM69 inhibited BDNF production in a PRKCD-dependent manner. Importantly, overexpression of PRKCD or BDNF blocked the effects of TRIM69 on the anoikis resistance and metastasis of GC cells. Interestingly, a TRIM69-PRKCD+BDNF+ cell subset was positively associated with metastasis in GC patients. TRIM69-mediated suppression of the anoikis resistance and metastasis of GC cells via modulation of the PRKCD/BDNF axis, with potential implications for novel therapeutic approaches for metastatic GC.

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Fig. 1: TRIM69 expression was low in anoikis-resistant GC cells.
Fig. 2: TRIM69 suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo.
Fig. 3: TRIM69 directly interacted with PRKCD.
Fig. 4: TRIM69 directly degraded PRKCD via the ubiquitin‒proteasome pathway.
Fig. 5: PRKCD is required for TRIM69 to suppress the anoikis resistance and metastasis of GC cells.
Fig. 6: The TRIM69/PRKCD axis inhibited anoikis resistance and metastasis via BDNF in GC cells.
Fig. 7: The proportion of TRIM69-PRKCD+BDNF+ cells was positively associated with metastasis in GC patients.
Fig. 8: The mechanisms by which TRIM69 suppresses GC anoikis resistance and metastasis.

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Data availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request. Moreover, we provide RNA-sequencing and IP-MS results in Supplementary Files 1 and 2.

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Acknowledgements

This work was supported by The National Natural Science Foundation of China (81802843,82073156,82270561,81872328); Key Research and Development Program of Jiangsu Province (BE2020656); The key project of Jiangsu Provincial Health and wellness Commission (ZD2021050); The Health Personnel Training Project of Suzhou (GSWS201903); Suzhou “Science and Education Revitalize Health” Youth Science and Technology Project (KJXW2022005).

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Authors and Affiliations

  1. Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Linqing Sun, Yuqi Chen, Lu Xia, Jiayu Wang, Jinghan Zhu, Juntao Li, Kun Wang, Kanger Shen, Dongze Zhang & Tongguo Shi

  2. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

    Linqing Sun, Yuqi Chen, Juntao Li, Guangbo Zhang & Tongguo Shi

  3. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China

    Linqing Sun, Yuqi Chen, Lu Xia, Jiayu Wang, Jinghan Zhu, Juntao Li, Kun Wang, Kanger Shen & Weichang Chen

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Contributions

The authors checked and approved the final manuscript. LQS, JYW, and JTL performed the experiments. LQS, YQC, and LX performed the data analysis. KW and KES performed sample collection and clinical evaluation. JHZ and DZZ provided guidance on experimental technology. GBZ, TGS, and WCC are the corresponding authors and they designed the research. The manuscript was wrote by LQS and revised by GBZ, TGS, and WCC.

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Correspondence to Guangbo Zhang, Tongguo Shi or Weichang Chen.

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Sun, L., Chen, Y., Xia, L. et al. TRIM69 suppressed the anoikis resistance and metastasis of gastric cancer through ubiquitin‒proteasome-mediated degradation of PRKCD. Oncogene 42, 3619–3632 (2023). https://doi.org/10.1038/s41388-023-02873-6

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