DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung.
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.
Shibata
T
T
Cancer Genomics Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. tashibat@ncc.go.jp
Kokubu
A
A
Miyamoto
M
M
Hosoda
F
F
Gotoh
M
M
Tsuta
K
K
Asamura
H
H
Matsuno
Y
Y
Kondo
T
T
Imoto
I
I
Inazawa
J
J
Hirohashi
S
S
D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics*; D016000:Cluster Analysis; D015536:Down-Regulation; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic
D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering