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Cellular and Molecular Biology

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

British Journal of Cancer volume 134, pages 860–873 (2026)Cite this article

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Abstract

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.

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Fig. 1: ACAP3 is frequently downregulated in LUAD tissues and cells with promoter hypermethylation.
Fig. 2: Myc inhibits ACAP3 expression in LUAD via promoting DNA methylation and histone deacetylation.
Fig. 3: ACAP3 inhibits cell proliferation via inducing cell cycle arrest.
Fig. 4: ACAP3 inhibits EGFR signalling pathway via accelerating its dynamic lysosomal degradation.
Fig. 5: ACAP3 promotes EGFR endosome trafficking toward late endocytosis.
Fig. 6: ACAP3 impairs EGFR endosome recycling.
Fig. 7: ACAP3 suppresses the proliferation and EGFR signal in LUAD cells depending on its GAP activity targeting ARF6.
Fig. 8: ACAP3 suppresses the growth of LUAD-derived xenograft tumours in vivo and serves as a positive prognostic marker for LUAD patients.

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Data availability

The datasets generated in the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank Haishan Huang and Yu Zhang for kindly supporting of materials.

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 82402714), Zhejiang Provincial Natural Science Foundation of China (Grant No. ZCLMS25H2001), the Medical and Health Science and Technology Program of Zhejiang Province (Grant No. 2024KY1243), Key Clinical Specialty Construction Project of Zhejiang Province, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province (Grant No. 2022E10022).

Author information

Author notes

  1. These authors contributed equally: Zhixiong Dong, Wenran Xie.

Authors and Affiliations

  1. Ningbo Institute of Innovation for Combined Medicine and Engineering, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, China; Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Zhixiong Dong & Yurui Zhang

  2. Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China; Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Wenran Xie

  3. Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Ningxin Zhang & Ying Guo

  4. Central Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Yangyang Liu

  5. Department of Thoracic Surgery, The Affiliated LiHuiLi Hospital of Ningbo University, Ningbo, China

    Chengbin Lin

  6. Department of Laboratory Medicine, Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Fanggui Shao

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Contributions

ZD: Methodology, Visualisation, Writing-Original draft preparation, Writing—Review & Editing, Supervision. WX: Methodology, Visualisation, Validation, Writing-Original draft preparation. NZ: Methodology, Investigation, Visualisation. YG: Methodology, Validation, Resources. YZ: Investigation, Resources. YL: Methodology, Investigation. CL: Validation, Conceptualisation, Writing—Review & Editing. FS: Resources, Funding acquisition, Writing—Review & Editing, Supervision.

Corresponding authors

Correspondence to Zhixiong Dong, Chengbin Lin or Fanggui Shao.

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Dong, Z., Xie, W., Zhang, N. et al. Myc-mediated epigenetic silencing of ACAP3 promotes lung adenocarcinoma proliferation via regulating EGFR dynamics. Br J Cancer 134, 860–873 (2026). https://doi.org/10.1038/s41416-025-03305-w

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