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E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice
Eva Moreno1, Mathilda J M Toussaint1, Saskia C van Essen1
1Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
Background And Aims:
Up-regulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking.
Approach And Results:
Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine-induced liver tumors.
Conclusion:
Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.
Insights
Atypical E2F proteins E2F7 and E2F8 repress transcription. Inducing these proteins in adult mice with cancer inhibited tumor cell proliferation, offering a potential therapeutic strategy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- E2F-dependent transcription is upregulated in most human cancers.
- E2F7 and E2F8 are atypical E2F proteins that repress transcription.
- Their in vivo function is poorly understood due to limited tools.
Purpose of the Study:
- To investigate the in vivo role of E2F7 and E2F8.
- To assess their potential as cancer therapeutics.
Main Methods:
- Generated transgenic mice with doxycycline-controlled E2f7 and E2f8 expression.
- Induced transgene expression during development, adulthood, and in liver tumors.
Main Results:
- E2F7/E2F8 induction in juvenile mice impaired growth, caused DNA damage, and apoptosis.
- In adult mice, induction was tolerated but inhibited liver tumor cell proliferation.
- E2F7 and E2F8 override cell-cycle progression controlled by other E2Fs.
Conclusions:
- Atypical E2Fs can inhibit proliferation of neoplastic cells.
- E2F7 and E2F8 hold therapeutic potential for adult cancers.
