Overexpression of the cellular DEK protein promotes epithelial transformation in vitro and in vivo.
High levels of expression of the human DEK gene have been correlated with numerous human malignancies. Intracellular DEK functions have been described in vitro and include DNA supercoiling, DNA replication, RNA splicing, and transcription. We have shown that DEK also suppresses cellular senescence, apoptosis, and differentiation, thus promoting cell growth and survival in monolayer and organotypic epithelial raft models. Such functions are likely to contribute to cancer, but direct evidence to implicate DEK as an oncogene has remained elusive. Here, we show that in line with an early role in tumorigenesis, murine papilloma formation in a classical chemical carcinogenesis model was reduced in DEK knockout mice. Additionally, human papillomavirus E6/E7, hRas, and DEK cooperated in the transformation of keratinocytes in soft agar and xenograft establishment, thus also implicating DEK in tumor promotion at later stages. Finally, adenoviral DEK depletion via short hairpin RNA expression resulted in cell death in human tumor cells in vitro and in vivo, but did not significantly affect differentiated epithelial cells. Taken together, our data uncover oncogenic DEK activities as postulated from its frequent up-regulation in human malignancies, and suggest that the targeted suppression of DEK may become a strategic approach to the treatment of cancer.
Wise-Draper
Trisha M
TM
Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Mintz-Cole
Rachael A
RA
Morris
Teresa A
TA
Simpson
David S
DS
Wikenheiser-Brokamp
Kathryn A
KA
Currier
Mark A
MA
Cripe
Timothy P
TP
Grosveld
Gerard C
GC
Wells
Susanne I
SI
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000209:etiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000235:genetics; D010212:Papilloma / Q000209:etiology; D050725:Papillomavirus E7 Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins / Q000235:genetics
D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; C068651:E6 protein, Human papillomavirus type 16; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16