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DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung

Oncogene volume 29, pages 4671–4681 (2010)Cite this article

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Abstract

Lung cancer shows diverse histological subtypes. Large-cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical behaviors, and can be classified as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Here we elucidated the molecular classification of pulmonary endocrine tumors by copy-number profiling. We compared alterations of copy number with the clinical outcome of HGNEC and identified a chromosomal gain of the DEK oncogene locus (6p22.3) that was significantly associated with poor prognosis. We further confirmed that DEK overexpression was associated with poor prognosis in a larger set of HGNEC. Downregulation of DEK by small hairpin RNA led to a marked reduction of in vitro colony formation, in vivo tumorigenicity and chemo-resistance, and was associated with loss of lung cancer stem cell markers. Gene expression profiling revealed that DEK downregulation was associated with altered expression of transcriptional regulators, which specifically include known targets of interchromosomal translocations in hematopoietic tumors, and knockdown of these epigenetic modifiers affected colony formation activity. Our study showed that DEK overexpression, partly through an increase in its gene dose, mediates the activity of global transcriptional regulators and is associated with tumor initiation activity and poor prognosis in HGNEC.

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Acknowledgements

We thank Dr Weixia Peng for the initial work of array CGH and Dr Yukihiro Yoshida for the help of clinical data analysis. We thank Dr S Diane Hayward at the Johns Hopkins University for generously providing the CBF1 reporter constructs (4xwtCBF1Luc and 4xmtCBF1Luc). This work was supported in part by Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, a grant from the New Energy and Industrial Technology Development Organization (NEDO), Japan and a grant for the program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio).

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Authors and Affiliations

  1. Cancer Genomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,

    T Shibata, A Kokubu, M Miyamoto, F Hosoda & S Hirohashi

  2. Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,

    T Shibata, M Gotoh & S Hirohashi

  3. Clinical Laboratory Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan,

    K Tsuta

  4. Division of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan,

    H Asamura

  5. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan,

    Y Matsuno

  6. Proteome Bioinfomatics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan,

    T Kondo

  7. Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan

    I Imoto & J Inazawa

  8. Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan

    I Imoto & J Inazawa

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  1. T Shibata
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Correspondence to T Shibata.

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Shibata, T., Kokubu, A., Miyamoto, M. et al. DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung. Oncogene 29, 4671–4681 (2010). https://doi.org/10.1038/onc.2010.217

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