Coordinated Controls of checkpoints and metabolism by E4F1 : cancer vulnerabilities ?

Orateur : Claude SARDET (Institut de Recherche en Cancérologie, Montpellier)

E4F1 was initially identified as a cellular transcription factor targeted by the adenoviral E1A oncoprotein. Its cellular activities remain poorly understood but are clearly essential for early embryogenesis, cell proliferation, differentiation or survival of various cell types. E4F1-/- mouse embryos die at the peri-implantation stage and exhibit mitotic progression defects, chromosomal missegregation and increased apoptosis. E4F1 is involved in several essential oncogenic pathways. It is targeted by viral oncoproteins and physically interacts with several bona fide cellular tumor suppressors and oncoproteins (RASSF1A, pRB, p14ARF, p53, Bmi1), suggesting that it might itself be involved in tumorigenesis. We also found that E4F1 is a multi-fonctional protein with an intrinsic transcriptional activity and an atypical ubiquitin E3-ligase activity that targets p53 : E4F1-mediated ubiquitylation of p53, instead of promoting p53 proteolysis, modulates p53 effector functions involved in alternative cell fates, growth arrest or apoptosis (Le Cam et al., Cell 2006). More recently, using conditional E4F1 KO mouse models with or without a functional p53 pathway, we observed that E4F1 also controls a p53-independent program essential for the survival of cancer cells and stem cells (Lacroix et al., PNAS 2010, Hatchi et al, J. Exp. Med. 2011). Acute E4F1 depletion in fully transformed Mefs or in leukemic cells results in p53-independent massive cell death associated with mitochondrial disfunctions, over-production of mitochondrial ROS an DNA damage. E4F1 target genes (110) have been identified using genome wide ChiP-seq analyses and expression profiling of E4F1 KO cells and animals (Rodier et al. Cell Reports 2015, Houlès et al Genomics Data 2015). E4F1 controls a small but essential set of genes important for mitochondrial homeostasis, energy metabolism (including a novel "PDH regulon"), nucleotide synthesis AND stress/checkpoint regulators, suggesting it coordinates metabolism and proliferation/survival. This E4F1 program identifies novel and unexpected synthetic lethalities between metabolic pathways and cell cycle/stress checkpoints that could be essential for cancer cells survival. We will present an example of such E4F1 KO-driven synthetic lethal strategy that kills efficiently transformed cells.

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