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

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

  • Br J Cancer. 2024 Jan 6. doi: 10.1038/s41416-023-02546-x.
Fenglin Cai # 1 2 3,  Xiuding Yang # 1,  Gang Ma # 1,  Pengliang Wang 4,  Mengmeng Zhang 1,  Nannan Zhang 5,  Rupeng Zhang 1,  Han Liang 1,  Yongzhan Nie 5,  Cheng Dong 6 7,  Jingyu Deng # 8
Affiliations

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.
  • 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.
  • 3 Department of Biochemistry and Molecular Biology, Tianjin Medical University, 300070, Tianjin, China.
  • 4 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 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.
  • 6 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. dongcheng@tmu.edu.cn.
  • 7 Department of Biochemistry and Molecular Biology, Tianjin Medical University, 300070, Tianjin, China. dongcheng@tmu.edu.cn.
  • 8 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. dengery@126.com.
  • # Contributed equally.
PMID: 38184692 DOI: 10.1038/s41416-023-02546-x
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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