Etude des modifications épigénétiques en fonction de l'agressivité du cancer sporadique du sein : l'implication de l'histone désacétylase SIRT1 dans la progression tumorale

Abstract : With 59,000 new cases in 2017, breast cancer is the most frequently diagnosed cancer among French women, and poses a real public health problem in France, but also worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis in different types of human cancers, including breast cancer. The deacetylase SIRT1 and the acetyltransferase TIP60 are 2 antagonistic epigenetic enzymes that are well implicated in apoptosis, gene regulation, genomic stability, DNA repair, and cancer development. In this manuscript, we identified the dysregulation of the histones H3 and H4 acetylation profiles in different molecular subtypes of sporadic breast cancer, and investigated the involvement of SIRT1 and TIP60 in breast tumorigenesis. First, we highlighted the roles of SIRT1 and TIP60 as potential prognostic biomarkers by revealing their differential expression patterns depending on breast cancer aggressiveness. Then, we demonstrated their differential epigenetic regulation of histone targets according to molecular subtype, and revealed their modulation of the H3K4ac epigenetic marker. Moreover, Epi-drugs mediated inhibition of these 2 enzymes has proven to be an effective strategy in the treatment of cancer. Thus, this work highlights the potential use of SIRT1 and TIP60 as epigenetic therapeutic targets for sporadic breast cancer.
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Khaldoun Rifai. Etude des modifications épigénétiques en fonction de l'agressivité du cancer sporadique du sein : l'implication de l'histone désacétylase SIRT1 dans la progression tumorale. Sciences agricoles. Université Clermont Auvergne, 2018. Français. ⟨NNT : 2018CLFAS011⟩. ⟨tel-02164095⟩

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