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Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis

Oncogene volume 36, pages 6863–6872 (2017)Cite this article

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Abstract

Lung cancer treatment remains a challenge for clinical practice and new therapeutic approaches are urgently needed. Loss of functional WEE1 kinase causes DNA replication stress, DNA damage and unscheduled mitotic entry due to elevated CDK activity. The selective WEE1 inhibitor MK-1775 synergize with DNA-damaging agent to inhibit cancer cell growth. Here we report that inhibition of Sirt1 deacetylase through small interfering RNA or selective inhibitor Ex527 greatly enhances MK-1775-induced growth inhibition and apoptosis in human lung cancer cells. We further demonstrate that Sirt1 interacts and deacetylates homologous recombination (HR) repair machinery proteins, including NBS1 and Rad51. Inhibition of Sirt1 impairs HR repair activity, which causes unrepairable damage when combining MK-1775 and Ex527. Meanwhile, combination of MK-1775 and Ex527 induces cooperative antitumor activity in lung cancer xenograft model in vivo. Thus, our study provides a novel therapeutic strategy to optimize MK-1775 treatment efficiency in lung cancers.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 81772010, 81571721 and 81301214), The National Basic Research and Development Program of China (973 Program; No. 2013CB733803) and Natural Science Basis Research Plan in Shaanxi Province of China (Program No. 2016JM8016 and 2013JQ4040).

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Author notes

  1. G Chen and B Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA

    G Chen, H Xu & Y Sun

  2. Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Medicine, Xi’an, China

    B Zhang

  3. Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi’an, China

    Y Shi & F Wang

  4. Department of Neurosurgery, Changhai Hospital, The Second Military Medical University, Shanghai, China

    Y Luo

  5. Department of Bioengineering, College of Food Science and Technology, Agricultural University of Hebei, Baoding, China

    H Jia

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  1. G Chen
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Correspondence to G Chen or F Wang.

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Chen, G., Zhang, B., Xu, H. et al. Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis. Oncogene 36, 6863–6872 (2017). https://doi.org/10.1038/onc.2017.297

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