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Cell Death Discovery
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c-Myc transactivates CFL1 to induce senescence-like phenotype and potentiate the bystander effects for the migration and proliferation in lung cancer cells
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  • Published: 26 March 2026

c-Myc transactivates CFL1 to induce senescence-like phenotype and potentiate the bystander effects for the migration and proliferation in lung cancer cells

  • Yen-Ting Chou1 na1,
  • Jyh-Der Leu2 na1,
  • Wan-Yu Yang1,
  • Chien-Hsiu Li3,4,
  • Min-Ying Lin  ORCID: orcid.org/0000-0002-2363-70851,
  • Chia-Wei Kao1,
  • Yu-Chan Chang1,
  • Michael Hsiao  ORCID: orcid.org/0000-0001-8529-92134,5 &
  • …
  • Yi-Jang Lee  ORCID: orcid.org/0000-0002-0340-75571,2,6 

Cell Death Discovery , Article number:  (2026) Cite this article

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Subjects

  • Oncogenes
  • Senescence

Abstract

Oncogene-induced senescence (OIS) is regarded a tumor suppressive mechanism in normal cells. Accumulated evidences, however, demonstrate that OIS would play a role in cancer promotion through the secretion of senescence associated secretory phenotypes (SASP). The underlying mechanisms remain to be addressed. In this study, we found that c-Myc oncogene could induce senescence in human diploid lung fibroblasts and non-small cell lung cancer cells (NSCLC) without concomitant emergence of apoptosis. c-Myc-induced senescence (cMIS) caused morphological enlargement, increased F-actin and nuclear G-actin that generally detected in senescent cells. These events were found to be associated with increased expression of cofilin-1, an actin-binding protein required for actin dynamics. Transfection of c-Myc could induce cofilin-1, but transfection of truncated Myc-Nick mutant and inhibition of c-Myc reduced cofilin-1 expression. Additionally, knockdown of cofilin-1 could suppress cMIS. The chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assay showed that the endogenous c-Myc mainly bound to two out of three predicted E-boxes located in middle and proximity to the transcription initiation site of the CFL1 promoter. Interestingly, ectopic expression of c-Myc bound to all E-boxes, especially the distal one. Furthermore, the conditioned medium (CM) collected from cells with cMIS could enhance the proliferation and migration of other NSCLC cells, whereas that obtained from cofilin-1 silencing cells with forced expression of c-Myc diminished these capacities. The c-Myc transactivated cofilin-1 could also be triggered by H2O2 through the middle E-box. Surprisingly, a physical interaction between c-Myc and cofilin-1 was detected, and H2O2 increased this effect. Clinically, high expression of both c-Myc and CFL1 genes correlated to worse survival rates among NSCLC patients, especially those with the adenocarcinoma subtype. Taken together, the c-Myc-cofilin-1 regulatory axis would explain the mechanism of OIS promoted cancer progression, and it may be a potent target for design of treatments.

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Acknowledgements

These works were supported by a grant of National Science and Technology Council of Taiwan (NSTC 111-2314-B-A49-037-MY3, NSTC 114-2314-B-A49 -065 -MY3), and a grant of Taipei City Hospital, RenAi Branch (TPCH-112-12), and grants from the Ministry of Education, Higher Education SPROUT Project for Cancer and Immunology Research Center (112W31101 and 113W031101). MRC-5 cells were kindly provided by Dr. Chien-Hsien Chen from Dept. of Bioengineering, Tatung University. We thank Mr. Guan Zeng for his assistance on raw data management. We thank Ms. Ke-Xin Huang, Ms. Chia-Chien Lo, and Ms. Bo-Han Huang for their technical supports.

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  1. These authors contributed equally: Yen-Ting Chou, Jyh-Der Leu.

Authors and Affiliations

  1. Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei Branch, Taipei, 112, Taiwan

    Yen-Ting Chou, Wan-Yu Yang, Min-Ying Lin, Chia-Wei Kao, Yu-Chan Chang & Yi-Jang Lee

  2. Division of Radiation Oncology, Taipei City Hospital Ren Ai Branch, Taipei, Taiwan

    Jyh-Der Leu & Yi-Jang Lee

  3. Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan

    Chien-Hsiu Li

  4. Genomics Research Center. Academia Sinica, Taipei, 11529, Taiwan

    Chien-Hsiu Li & Michael Hsiao

  5. Department and Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, 112, Taiwan

    Michael Hsiao

  6. Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei Branch, Taipei, 112, Taiwan

    Yi-Jang Lee

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Chou, YT., Leu, JD., Yang, WY. et al. c-Myc transactivates CFL1 to induce senescence-like phenotype and potentiate the bystander effects for the migration and proliferation in lung cancer cells. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03065-3

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  • Received: 28 November 2025

  • Revised: 23 February 2026

  • Accepted: 09 March 2026

  • Published: 26 March 2026

  • DOI: https://doi.org/10.1038/s41420-026-03065-3

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Cell Death Discovery (Cell Death Discov.)

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