Targeting the COMMD4-H2B protein complex in lung cancer.

Autor: Tang M; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.; Frazer Institute, Faculty of Medicine, The University of Queensland at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia., Burgess JT; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia., Fisher M; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia., Boucher D; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia., Bolderson E; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia., Gandhi NS; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.; Department of Computer Science and Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, 576104, India., O'Byrne KJ; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia. k.obyrne@qut.edu.au.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia. k.obyrne@qut.edu.au., Richard DJ; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia. derek.richard@qut.edu.au.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia. derek.richard@qut.edu.au., Suraweera A; Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia. amila.suraweera@qut.edu.au.; Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD, 4102, Australia. amila.suraweera@qut.edu.au.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2023 Dec; Vol. 129 (12), pp. 2014-2024. Date of Electronic Publication: 2023 Nov 01.
DOI: 10.1038/s41416-023-02476-8
Abstrakt: Background: Lung cancer is the biggest cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers. Identification of novel therapeutic targets are required as drug resistance impairs chemotherapy effectiveness. COMMD4 is a potential NSCLC therapeutic target. The aims of this study were to investigate the COMMD4-H2B binding pose and develop a short H2B peptide that disrupts the COMMD4-H2B interaction and mimics COMMD4 siRNA depletion.
Methods: Molecular modelling, in vitro binding and site-directed mutagenesis were used to identify the COMMD4-H2B binding pose and develop a H2B peptide to inhibit the COMMD4-H2B interaction. Cell viability, DNA repair and mitotic catastrophe assays were performed to determine whether this peptide can specially kill NSCLC cells.
Results: Based on the COMMD4-H2B binding pose, we have identified a H2B peptide that inhibits COMMD4-H2B by directly binding to COMMD4 on its H2B binding binding site, both in vitro and in vivo. Treatment of NSCLC cell lines with this peptide resulted in increased sensitivity to ionising radiation, increased DNA double-strand breaks and induction of mitotic catastrophe in NSCLC cell lines.
Conclusions: Our data shows that COMMD4-H2B represents a novel potential NSCLC therapeutic target.
(© 2023. The Author(s).)
Databáze: MEDLINE
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