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The E3 ubiquitin ligase HUWE1 is required for KRAS-induced lung cancer
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  • Published: 07 April 2026

The E3 ubiquitin ligase HUWE1 is required for KRAS-induced lung cancer

  • J. Searle  ORCID: orcid.org/0000-0002-1055-02471,2 nAff5,
  • M. Menotti1,2,
  • W. J. McDaid2,3,
  • M. J. Baker2,3,
  • A. Chaturvedi2,4,
  • L. Ginn1,2,
  • H. Reed1,2,
  • M. Carter2,4,
  • F. Blackhall2,3,4,
  • C. R. Lindsay2,3,4 na1 &
  • …
  • A. Malliri1,2,3 na1 

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

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Non-small-cell lung cancer
  • Ubiquitylation

Abstract

The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples, we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of LUAD initiation and growth, we identify that Huwe1 is essential for mutant Kras-induced lung tumour development and reveal a novel, p53-independent requirement for Huwe1 in LUAD. Mechanistically, we demonstrate induction of senescence following HUWE1 depletion - characterised by impaired proliferation, an atypical cell cycle distribution, emergence of morphologically abnormal enlarged cells, increased β-galactosidase activity, and transcriptional reprogramming associated with inflammatory senescence-associated secretory phenotype (SASP) signalling and NFκB activation. Together, these data highlight a crucial role for HUWE1 in mutant Kras-induced LUAD tumorigenesis and in the continued growth and proliferation of established LUAD cells, confirming HUWE1 as a rational therapeutic target for LUAD.

Data availability

The RNA-seq data reported in this paper have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE290690. All other data are included in the manuscript and/or supporting material.

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Acknowledgements

We are grateful to the core facilities of the Cancer Research UK (CRUK) Manchester Institute for their support with experimental work, including the Biological Research Unit (BRU), Transgenic breeding facility, Flow Cytometry, Histology, Visualisation and Analysis, Molecular Biology, and Computational Biology facilities. We thank Professor Ilaria Malanchi (Francis Crick Institute) for providing the Sftpc-Cre-ERT2 allele, and Professor Owen Sansom (CRUK Scotland Institute) for providing HUWE1Flox/Flox mice. Schematic diagrams in Fig. 2A, 2E, 3F, and S6B created using publicly-available illustrations from NIAID Visual & Medical Arts (NIH BioArt): Human Lungs (bioart.niaid.nih.gov/bioart/231) and Syringe (bioart.niaid.nih.gov/bioart/506), and from Scidraw: Mouse (10.5281/zenodo.3925900).

Funding

CRL was supported by the IASLC (Young Investigator Award) and the Manchester Cancer Research Centre Town Hall Programme. This work was also supported by core funding to the CRUK Manchester Institute (CRUK MI) (grant A27412), Manchester CRUK Centre Award (grant A25254), CRUK Manchester Experimental Cancer Medicines Centre (grant A25146), CRUK Lung Cancer Centre of Excellence (Grant A20465), and by The Christie Charitable Fund.

Author information

Author notes

  1. J. Searle

    Present address: Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London (UCL), London, UK

  2. These authors contributed equally: C. R. Lindsay, A. Malliri.

Authors and Affiliations

  1. Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    J. Searle, M. Menotti, L. Ginn, H. Reed & A. Malliri

  2. Cancer Research UK Lung Cancer Centre of Excellence, The University of Manchester, Manchester, UK

    J. Searle, M. Menotti, W. J. McDaid, M. J. Baker, A. Chaturvedi, L. Ginn, H. Reed, M. Carter, F. Blackhall, C. R. Lindsay & A. Malliri

  3. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    W. J. McDaid, M. J. Baker, F. Blackhall, C. R. Lindsay & A. Malliri

  4. The Christie NHS Foundation Trust, Manchester, UK

    A. Chaturvedi, M. Carter, F. Blackhall & C. R. Lindsay

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Contributions

Conceptualization, JS, MM, AM; methodology, JS, MM, WJM, LG, HR; validation and data curation, JS, MJB; formal analysis and investigation, JS, MM, W.JM, MJB, AC; resources, MC, FB, CRL, AM; writing–original draft, JS, AM; writing–review & editing, JS, CRL, AM; visualization, JS, AM; funding acquisition and supervision, CRL, AM.

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Correspondence to J. Searle or A. Malliri.

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All animal procedures were carried out in accordance with the Home Office Regulations (UK) and the UK Coordinating Committee on Cancer Research guidelines using approved protocols and following ethical review (Home Office Project license numbers: 70/8386 and PP5790814, and Cancer Research UK Manchester Institute Animal Welfare and Ethical Review Advisory Body). Human patient tissue samples were sourced from the ETOP (European Thoracic Oncology Platform) Lungscape study (ethical approval: REC Ref 12/LO/0235) and ChemoRes (Molecular mechanisms underlying chemotherapy resistance, therapeutic escape, efficacy, and toxicity) study (ethical approval: REC Ref 07/H1014/96), in which informed consent was obtained from all participants prior to sample collection.

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Searle, J., Menotti, M., McDaid, W.J. et al. The E3 ubiquitin ligase HUWE1 is required for KRAS-induced lung cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08672-7

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  • Received: 20 March 2025

  • Revised: 18 February 2026

  • Accepted: 13 March 2026

  • Published: 07 April 2026

  • DOI: https://doi.org/10.1038/s41419-026-08672-7

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