Discovery of Tissue-Specific Functions of Atypical E2Fs in Cancer

PhD thesis, Eva Moreno Iglesias

The cell cycle control system ensures that the genome is properly duplicated and evenly distributed over the daughter cells. This system is highly conserved and regulated by a plethora of genes. Among this regulatory system is the Rb-E2F network, which controls the expression of key cell cycle genes. Thus, it is not surprising that Rb is often lost or mutated in cancer, resulting in hyperactivated E2F transcription and enhanced tumorigenesis. To counteract enhanced E2F transcription, alternative mechanisms that inhibit E2F transcription to efficiently block proliferation of cancer cells are needed.

In this thesis, we manipulated E2F-dependent transcription by altering the expression of E2F7 and E2F8 in mouse models. E2F7/8 are atypical cell cycle inhibitors belonging to the E2F family that possess Rb-independent repressive function. We hypothesized that overactivation of atypical E2F repressors efficiently blocks cancer cell proliferation. The studies from this thesis demonstrated that downregulation of E2F transcription by boosting E2F7/8 expression impaired the ability of liver cancer cells to progress through the cell cycle and suppressed tumor growth. In addition, unrestrained E2F dependent transcription due to loss of atypical E2Fs and RB, induced tumorigenesis in a tissue cell-type specific manner via a mechanism that involves maintenance of genomic instability. Lastly, we unravel novel functions of atypical E2Fs in lipid metabolism by controlling liver polyploidization.

Taken together, this thesis has contributed to our understanding of the role of atypical E2Fs and Rb in cancer and provides scientific evidence that inhibition of E2F-depedent transcription could be a novel therapeutic option in oncology.