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A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness

Oncogene volume 36, pages 6919–6928 (2017)Cite this article

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Abstract

Overexpression of DNMT1 and KIT is prevalent in lung cancer, yet the underlying molecular mechanisms are poorly understood. While the deregulated activation of DNMT1 or KIT has been implicated in lung cancer pathogenesis, whether and how DNMT1 and KIT orchestrate lung tumorigenesis are unclear. Here, using human lung cancer tissue microarrays and fresh frozen tissues, we found that the overexpression of DNMT1 is positively correlated with the upregulation of KIT in tumor tissues. We demonstrated that DNMT1 and KIT form a positive regulatory loop, in which ectopic DNMT1 expression increases, whereas targeted DNMT1 depletion abrogates KIT signaling cascade through Sp1/miR-29b network. Conversely, an increase of KIT levels augments, but a reduction of KIT expression ablates DNMT1 transcription by STAT3 pathway leading to in-parallel modification of the DNA methylation profiles. We provided evidence that KIT inactivation induces global DNA hypomethylation, restores the expression of tumor suppressor p15INK4B through promoter demethylation; in turn, DNMT1 dysfunction impairs KIT kinase signaling. Functionally, KIT and DNMT1 co-expression promotes, whereas dual inactivation of them suppresses, lung cancer cell proliferation and metastatic growth in vitro and in vivo, in a synergistic manner. These findings demonstrate the regulatory and functional interplay between DNA methylation and tyrosine kinase signaling in propelling tumorigenesis, providing a widely applicable approach for targeting lung cancer.

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Acknowledgements

This work was supported in part by Hormel Foundation (S. Liu) and National Cancer Institute (Bethesda, MD, USA) grants R01CA149623 (S. Liu) and R21CA155915 (S. Liu).

Author contributions

SL designed the research; FY, NS, JP, NZ and BD performed research; YY, PY and JRM provided the patient samples; FY, BL, PY, JRM and SL analyzed data and wrote the paper; SL conceived the idea and supervised the whole project. All authors discussed the results and commented on the manuscript.

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Author notes

  1. F Yan and N Shen: These authors contributed equally to this work.

Authors and Affiliations

  1. The Hormel Institute, University of Minnesota, Austin, MN, USA

    F Yan, N Shen, J Pang, N Zhao & S Liu

  2. Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

    B Deng, Y Yang & P Yang

  3. Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA

    B Li

  4. Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA

    J R Molina

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  1. F Yan
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Correspondence to S Liu.

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Yan, F., Shen, N., Pang, J. et al. A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness. Oncogene 36, 6919–6928 (2017). https://doi.org/10.1038/onc.2017.305

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