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DEK proto-oncogene expression interferes with the normal epithelial differentiation program
Trisha M Wise-Draper1, Richard J Morreale, Teresa A Morris
1Division of Pediatric Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Abstract:
Overexpression of the DEK gene is associated with multiple human cancers, but its specific roles as a putative oncogene are not well defined. DEK transcription was previously shown to be induced by the high-risk human papillomavirus (HPV) E7 oncogene via E2F and Rb pathways. Transient DEK overexpression was able to inhibit both senescence and apoptosis in cultured cells. In at least the latter case, this mechanism involved the destabilization of p53 and the decreased expression of p53 target genes. We show here that DEK overexpression disrupts the normal differentiation program in a manner that is independent of either p53 or cell death. DEK expression was distinctly repressed upon the differentiation of cultured primary human keratinocytes, and stable DEK overexpression caused epidermal thickening in an organotypic raft model system. The observed hyperplasia involved a delay in keratinocyte differentiation toward a more undifferentiated state, and expansion of the basal cell compartment was due to increased proliferation, but not apoptosis. These phenotypes were accompanied by elevated p63 expression in the absence of p53 destabilization. In further support of bona fide oncogenic DEK activities, we report here up-regulated DEK protein levels in both human papilloma virus-positive hyperplastic murine skin and a subset of human squamous cell carcinomas. We suggest that DEK up-regulation may contribute to carcinoma development at least in part through increased proliferation and retardation of differentiation.
Insights
Overexpression of the DEK gene disrupts normal cell differentiation and promotes proliferation, contributing to skin hyperplasia and potentially cancer development. This occurs independently of p53 pathways, highlighting DEK
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- DEK gene overexpression is linked to various human cancers.
- The DEK oncogene's precise role in cancer is not fully understood.
- DEK transcription is induced by human papillomavirus (HPV) E7 oncogene.
Purpose of the Study:
- To investigate the role of DEK overexpression in cellular differentiation and proliferation.
- To determine if DEK's effects are dependent on p53 or apoptosis pathways.
- To examine DEK protein levels in HPV-associated skin conditions and squamous cell carcinomas.
Main Methods:
- Studied DEK expression during keratinocyte differentiation.
- Utilized an organotypic raft model to assess epidermal hyperplasia from stable DEK overexpression.
- Analyzed p53 and p63 expression in DEK-overexpressing models.
- Examined DEK protein levels in HPV-positive murine skin and human squamous cell carcinomas.
Main Results:
- DEK expression is repressed during normal keratinocyte differentiation.
- Stable DEK overexpression caused epidermal thickening and delayed keratinocyte differentiation.
- DEK overexpression led to increased proliferation and basal cell expansion, independent of p53 destabilization.
- Elevated p63 expression was observed with DEK overexpression.
- Increased DEK protein levels were found in HPV-positive hyperplastic skin and a subset of squamous cell carcinomas.
Conclusions:
- DEK overexpression disrupts normal differentiation and promotes proliferation, contributing to skin hyperplasia.
- DEK's oncogenic activity in this context is independent of p53 destabilization.
- DEK up-regulation may drive carcinoma development by increasing proliferation and hindering differentiation.
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