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

T. Shibata, A. Kokubu, M. Miyamoto, F. Hosoda, M. Gotoh, K. Tsuta, Hisao Asamura, Y. Matsuno, T. Kondo, I. Imoto, J. Inazawa, S. Hirohashi

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4671-4681
Number of pages11
JournalOncogene
Volume29
Issue number33
DOIs
Publication statusPublished - 2010 Aug 19
Externally publishedYes

Fingerprint

Neuroendocrine Carcinoma
Oncogene Proteins
Lung
Neoplasms
Lung Neoplasms
Down-Regulation
Large Cell Carcinoma
Neuroendocrine Cells
Neoplastic Stem Cells
Small Cell Lung Carcinoma
Gene Expression Profiling
Oncogenes
Epigenomics
Small Interfering RNA
Genes

Keywords

  • cancer stem cell
  • DEK
  • lung cancer
  • neuroendocrine

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

Cite this

DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung. / Shibata, T.; Kokubu, A.; Miyamoto, M.; Hosoda, F.; Gotoh, M.; Tsuta, K.; Asamura, Hisao; Matsuno, Y.; Kondo, T.; Imoto, I.; Inazawa, J.; Hirohashi, S.

In: Oncogene, Vol. 29, No. 33, 19.08.2010, p. 4671-4681.

Research output: Contribution to journalArticle

Shibata, T, Kokubu, A, Miyamoto, M, Hosoda, F, Gotoh, M, Tsuta, K, Asamura, H, Matsuno, Y, Kondo, T, Imoto, I, Inazawa, J & Hirohashi, S 2010, 'DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung', Oncogene, vol. 29, no. 33, pp. 4671-4681. https://doi.org/10.1038/onc.2010.217
Shibata, T. ; Kokubu, A. ; Miyamoto, M. ; Hosoda, F. ; Gotoh, M. ; Tsuta, K. ; Asamura, Hisao ; Matsuno, Y. ; Kondo, T. ; Imoto, I. ; Inazawa, J. ; Hirohashi, S. / DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung. In: Oncogene. 2010 ; Vol. 29, No. 33. pp. 4671-4681.
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