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Background <p>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.</p> Methods <p>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 <i>ArfGAP with coiled-coil, ankyrin repeat and PH domains 3</i> (<i>ACAP3</i>) in LUAD carcinogenesis were further investigated.</p> Results <p>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.</p> Conclusion <p>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.</p>

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Myc-mediated epigenetic silencing of ACAP3 promotes lung adenocarcinoma proliferation via regulating EGFR dynamics

  • 期刊论文

  • 发表日期：

    2026年1月10日

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  • Zhixiong Dong,
  • Wenran Xie,
  • Ningxin Zhang,
  • Ying Guo,
  • Yurui Zhang,
  • Yangyang Liu,
  • Chengbin Lin,
  • Fanggui Shao

摘要

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.