Myc-mediated epigenetic silencing of ACAP3 promotes lung adenocarcinoma proliferation via regulating EGFR dynamics
Menée à l'aide de lignées cellulaires, de xénogreffes sur un modèle murin ainsi que d'échantillons tumoraux et d'échantillons tissulaires adjacents issus de patients atteints d'un adénocarcinome du poumon, cette étude met en évidence un mécanisme par lequel la protéine ACAP3, dont l'expression est affectée épigénétiquement par Myc, supprime la prolifération des cellules cancéreuses en inhibant la signalisation du récepteur EGFR
Background : Despite significant advances in diagnosis and therapy, the prognosis of late-stage lung adenocarcinoma (LUAD) remains poor, underscoring the urgent need for effective biomarkers to enable early detection. Epigenetic alterations, particularly DNA methylation, is essential for controlling gene expression, and its abnormality plays critical roles in promoting carcinogenesis.
Methods : Reduced representation bisulfite sequencing (RRBS) technique was used to establish the DNA methylation profile in early-stage LUAD in comparison to normal tissues. The epigenetic abnormalities and expression, as well as the functions of ArfGAP with coiled-coil, ankyrin repeat and PH domains 3 (ACAP3) in LUAD carcinogenesis were further investigated.
Results : we investigated the DNA methylation dysregulation during tumorigenesis in the early-stage LUAD, and identified that Myc-mediated DNA hypermethylation and deacetylation as key mechanisms suppressing ACAP3 expression. ACAP3 significantly suppresses the proliferation of LUAD cells in vitro and in vivo. Mechanically, ACAP3 inhibits epidermal growth factor receptor (EGFR) signalling via impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GTPase-activating protein (GAP) activity-dependent manner.
Conclusion : Our finding reveals that ACAP3, suppressed by Myc-mediated epigenetic abnormality in early-stage LUAD, acts as a tumour suppressor by inhibiting EGFR signalling and cells proliferation, suggesting its potential as a diagnostic and therapeutic target.
British Journal of Cancer , article en libre accès, 2026