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Implication de glycosyltransférases dans la tumorigenèse colorectale : POFUT1 et ST3GAL2

Abstract : Colorectal cancer is a global health problem characterized by numerous gene alterations, including changes in the expression of glycosyltransferases. The protein O-fucosyltransferase 1 (POFUT1) is overexpressed in several tumor types, including gastric, liver, breast and colorectal tumors. This enzyme catalyzes the transfer of an O-fucose onto a serine or threonine of EGF-like motifs, according to a consensus O-fucosylation sequence C2-X1-4-S/T-C3. POFUT1 target proteins have been identified on the presence of this consensus sequence, the most studied being the membrane receptor NOTCH. In colorectal tumors, overexpression is due to an amplification of the 20q11.21 chromosomal region in which the POFUT1 gene is located. In rare cases where POFUT1 is neither overexpressed nor amplified, 7 mutations are found in the coding sequence of POFUT1 without knowing the consequences. This work reveals that 6 of the 7 recombinantly produced POFUT1 protein variants have significantly higher in vitro O-fucosylation activities in vitro than the wild-type form of the enzyme, more particularly on the EGF motif 26 of the NOTCH receptor. These results suggest that patients with these POFUT1 mutations have a higher O-fucosylation activity that would promote tumorigenesis via NOTCH signaling pathway, among others.After an extensive study of sialyltransferase expression in RNA-Seq databases, ST3GAL2 was found to be the only gene encoding a sialyltransferase significantly overexpressed in colorectal tumors. Our works shows that a KD of ST3GAL2 in a colorectal cancer line results in a significant decrease in cell proliferation, migration and invasion capacities, a change in cell cycle distribution and an increase in cell death by apoptosis in vitro. Xenografts of these same cells in mice show that the KD of ST3GAL2 slows tumor progression. We show that the KD of ST3GAL2, alters the ⍺2-3 sialylation of glycolipids as well as membrane glycoproteins. ST3GAL2 could be considered a novel oncogene involved, along with POFUT1, in colorectal tumorigenesis. Both would share a common regulator, SMC1A, also overexpressed in colorectal tumors, able of binding to both gene sequences to promote their expression.
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Submitted on : Thursday, November 24, 2022 - 1:01:44 AM
Last modification on : Wednesday, November 30, 2022 - 3:33:08 PM

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  • HAL Id : tel-03868788, version 1

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Marlene Deschuyter. Implication de glycosyltransférases dans la tumorigenèse colorectale : POFUT1 et ST3GAL2. Médecine humaine et pathologie. Université de Limoges, 2021. Français. ⟨NNT : 2021LIMO0065⟩. ⟨tel-03868788⟩

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