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

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un cancer de l'estomac, cette étude met en évidence un mécanisme non enzymatique par lequel le facteur EGLN3 atténue l'agressivité des cellules cancéreuses en inhibant l'activation de la voie de signalisation JMJD8/NF-kappaB

Résumé en anglais

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-