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Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer

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Abstract

Alteration of O-GlcNAcylation, a dynamic posttranslational modification, is associated with tumorigenesis and tumor progression. Its role in chemotherapy response is poorly investigated. Standard treatment for colorectal cancer (CRC), 5-fluorouracil (5-FU), mainly targets Thymidylate Synthase (TS). TS O-GlcNAcylation was reported but not investigated yet. We hypothesize that O-GlcNAcylation interferes with 5-FU CRC sensitivity by regulating TS. In vivo, we observed that combined 5-FU with Thiamet-G (O-GlcNAcase (OGA) inhibitor) treatment had a synergistic inhibitory effect on grade and tumor progression. 5-FU decreased O-GlcNAcylation and, reciprocally, elevation of O-GlcNAcylation was associated with TS increase. In vitro in non-cancerous and cancerous colon cells, we showed that 5-FU impacts O-GlcNAcylation by decreasing O-GlcNAc Transferase (OGT) expression both at mRNA and protein levels. Reciprocally, OGT knockdown decreased 5-FU-induced cancer cell apoptosis by reducing TS protein level and activity. Mass spectrometry, mutagenesis and structural studies mapped O-GlcNAcylated sites on T251 and T306 residues and deciphered their role in TS proteasomal degradation. We reveal a crosstalk between O-GlcNAcylation and 5-FU metabolism in vitro and in vivo that converges to 5-FU CRC sensitization by stabilizing TS. Overall, our data propose that combining 5-FU-based chemotherapy with Thiamet-G could be a new way to enhance CRC response to 5-FU.

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Fig. 1: O-GlcNAcylation sensitizes CRC to 5-FU chemotherapy in vivo.
Fig. 2: 5-FU decreases OGT and O-GlcNAcylation levels in noncancerous and cancerous cells.
Fig. 3: Knockdown of OGT reduces 5-FU sensitivity of cancer cells by decreasing TS target levels.
Fig. 4: OGT interacts with and O-GlcNAcylates TS.
Fig. 5: O-GlcNAcylation at T251 and T306 increases TS stability by preventing its proteasomal degradation.
Fig. 6: O-GlcNAcylation at T251 and T306 increases TS dimer stabilization by generating intra- and inter-monomer interactions.

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Data availability

Microarray GSE104645 data are available in the Gene Expression Omnibus (GEO) repository.

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Acknowledgements

This work was supported by the “Ligue Contre le Cancer/Comité du Nord/Comité de la Somme”, the “Région Hauts-de-France” (Cancer Regional Program), the University of Lille and the “Center National de la Recherche Scientifique”. NV is the recipient of a fellowship from the “Ministère de l’Enseignement Supérieur et de la Recherche”. The authors acknowledge the financial support from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences and Health) within the framework of the cancer plan for Orbitrap mass spectrometer funding. We thank Dr. Guillemette Huet (CANTHER UMR9020 UMR1277, Lille, France) for HT-29 5F31 cell line [26], Dr. Matthew G. Alteen (Department of Chemistry, Simon Fraser University, Canada) for Thiamet-G and Dr. Cyril Couturier (UMR8090 IBL, Lille, France) for pcDNA3.1-Ub-HA plasmid gifts.

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Authors and Affiliations

  1. Université de Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000, Lille, France

    Ninon Very, Stéphan Hardivillé, Céline Schulz, Tony Lefebvre & Ikram El Yazidi-Belkoura

  2. Université de Lille, CNRS, INSERM, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000, Lille, France

    Amélie Decourcelle & Vanessa Dehennaut

  3. Universté de Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1190—EGID, F-59000, Lille, France

    Julien Thévenet & Julie Kerr-Conte

  4. Université de Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research In Inflammation, F-59000, Lille, France

    Madjid Djouina & Gérard Vergoten

  5. Protein Science Facility, CNRS UMS3444, INSERM US8, UCBL, ENS de Lyon, SFR BioSciences, Lyon, France

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  1. Ninon Very
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Contributions

NV designed, performed, and analyzed in vitro and in vivo experiment data and co-wrote the paper. SH performed plasmid constructions and PEG synthesis and co-wrote the paper. AD contributed to the in vivo experiments. JKC contributed to the in vivo experiment design and the reviewing of the paper. JT contributed to the in vivo experiments. MD performed mice colonoscopy and contributed to the IHC experiments. AP performed mass spectrometry analyzes. GV performed TS structure modeling in silico analysis. CS performed microscopy acquisition of fluorescence images of immunocytochemistry experiments. TL contributed to discussions and reviewed the paper. VD contributed to the work design, the experiments, the data analysis and the reviewing of the paper. IEB supervised and conceptualized the research, contributed to the experiments and data analyzes, and co-wrote the paper. All authors read and approved the paper.

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Correspondence to Ikram El Yazidi-Belkoura.

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Very, N., Hardivillé, S., Decourcelle, A. et al. Thymidylate synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer. Oncogene 41, 745–756 (2022). https://doi.org/10.1038/s41388-021-02121-9

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