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Etude du rôle du corégulateur transcriptionnel RIP140 dans le métabolisme glucidique et la différenciation des cellules cancéreuses

Abstract : Metabolic reprogramming is a hallmark of cancer cells that are capable, among other things, of going from an aerobic metabolism (oxidative phosphorylation) to an anaerobic metabolism (glycolysis) according to their needs. This allows them to survive in nutrient-poor environments and to resist to certain anti-cancer treatments. Explaining the mechanisms responsible for the metabolic reprogramming of cancer cells could lead to the development of new cancer therapies. My thesis project aims to decipher the role of the transcriptional coregulator RIP140 in cancer cell metabolic flexibility and chemoresistance. RIP140 (Receptor Interacting Protein of 140 Kda) is a trancriptionnal coregulator that interact with various transcription factors (nuclear receptor, factors such as AP-1, SP1, NF-KB et E2F1, etc.) in order to regulate gene expression. Thanks to its large interactome, it is implicated in the regulation of various physiological and pathophysiological processes such as metabolism or cancer, respectively. In this context we were interested in the potential role of RIP140 control in cancer metabolism. We demonstrate that the loss of RIP140 expression in transformed mouse embryonic fibroblasts (MEF RIPKO) increase cell proliferation, tumor growth and glycolysis. Moreover, this proliferative advantage is abrogated by glucose deprivation or glycolysis inhibition with pharmacological agent in vitro and in vivo in xenografted mice. We also show that glycolysis gene such as GLUT3 or G6PD are upregulated in RIPKO MEF and that cell proliferation is dependent of their expression. We confirmed those results in cancer cell lines showing a general effect of RIP140 on cancer cells metabolism. Chromatin immunoprecipitation experiment show that RIP140 is present at GLUT3 gene promotor. Our data establish for the first time RIP140 as a critical modulator of the transcriptional interplay between HIF2α (Hypoxia Inducible Factor 2α) and p53 in the control of glucose metabolism in cancer cells. In parallel, I was interested in the role of RIP140 in the chemoresistance of acute myeloid leukemia (AML) whose frequent relapses can be due to a metabolic reprogramming enhancing oxidative phosphorylation metabolism. We show that, in contrast to solid tumors, high expression of RIP140 is associated with a poor prognosis in AML. Modulation of RIP140 expression in AML cell lines using shRNA induces a decrease of proliferation via apoptosis control. RNAseq data established on OCI-AML2 where RIP140 expression was reduce compared to control show that RIP140 is implicated in the regulation of apoptosis, cell cycle, oxidative phosphorylation and retinoic acid metabolism. The next step was to test AML cells sensitivity to all trans retinoic acid (ATRA), a differentiating agent, when RIP140 expression was depressed. We show that RIP140 inhibition potentiates ATRA effects on AML cells. The overall results will determine the involvement of RIP140 in AML chemoresistance. At the end, this factor could be proposed as a predictive marker of response to treatments for this pathology.
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Submitted on : Friday, September 10, 2021 - 11:07:07 AM
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Valentin Jacquier. Etude du rôle du corégulateur transcriptionnel RIP140 dans le métabolisme glucidique et la différenciation des cellules cancéreuses. Sciences agricoles. Université Montpellier, 2020. Français. ⟨NNT : 2020MONTT084⟩. ⟨tel-03340471⟩

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