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Cellular and Molecular Biology

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity

British Journal of Cancer volume 130, pages 597–612 (2024)Cite this article

Subjects

Abstract

Background

The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3.

Methods

This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3.

Results

EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity.

Conclusions

EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.

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Fig. 1: EGLN3 expression decreases in GC tissues and GC cell lines, which indicates poor patient outcome.
Fig. 2: Promoter hypermethylation inhibits EGLN3 expression in GC cells.
Fig. 3: The tumour suppression effect of EGLN3 in GC is independent on its catalytic activity.
Fig. 4: EGLN3 reduces the expression of JMJD8.
Fig. 5: JMJD8 knockdown inhibits the propagation in GC cells and the tumour suppression effect of EGLN3 is dependent on JMJD8 depletion.
Fig. 6: EGLN3 attenuate GC cell malignant characteristics via inhibiting JMJD8/NF-κB signalling activation.

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Data availability

GSE200646 (GEO database).

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Acknowledgements

Thanks for all help.

Funding

This work was jointly funded by the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), the Distinguished professor of Tianjin (JTZB [2019] No.120), the Programs of National Natural Science Foundation of China (No. 81572372), the National Natural Science Foundation of China (81974373).

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Author notes

  1. These authors contributed equally: Fenglin Cai, Xiuding Yang, Gang Ma, Jingyu Deng.

Authors and Affiliations

  1. Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer; Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, China

    Fenglin Cai, Xiuding Yang, Gang Ma, Mengmeng Zhang, Rupeng Zhang, Han Liang & Jingyu Deng

  2. The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Haihe Laboratory of Cell Ecosystem, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China

    Fenglin Cai & Cheng Dong

  3. Department of Biochemistry and Molecular Biology, Tianjin Medical University, 300070, Tianjin, China

    Fenglin Cai & Cheng Dong

  4. Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Pengliang Wang

  5. State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China

    Nannan Zhang & Yongzhan Nie

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Contributions

FC and JD were major contributors to the design of this study and drafted the manuscript. GM, YN, CD and JD supported the research techniques. NZ, XY, PW, and MZ were responsible for tissue collection. RZ, HL and JD were responsible for clinical databases. JD designed this study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cheng Dong or Jingyu Deng.

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Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

The use of specimens from patients were approved by the Institutional Research Ethics Committee of Tianjin Medical University Cancer Institute and Hospital (no. bc2020091, date: 27 July 2020) (Tianjin, China). Informed consent was obtained for the collection of all samples in accordance with the Declaration of Helsinki. All experimental animal procedures were carried out with the approval of the Institutional Animal Care and Research Advisory Committee of Tianjin Medical University (Tianjin, China) under grant no. AE-2021073 (date: 11 October 2021).

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Cai, F., Yang, X., Ma, G. et al. EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity. Br J Cancer 130, 597–612 (2024). https://doi.org/10.1038/s41416-023-02546-x

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