Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression
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BACKGROUND & AIMS: Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown. METHODS: We examined the alterations in histone modifications in patient-derived colorectal cancer organoids. Patient-derived colorectal cancer organoids and mouse intestinal organoids were genetically manipulated for functional studies in patient-derived xenograft and orthotopic transplantation. Gene expression profiling, micrococcal nuclease assay, and chromatin immunoprecipitation were performed to understand epigenetic regulation of chromatin states and gene expression in patient-derived and mouse intestinal organoids. RESULTS: We found that reduced H4K20me3 levels occurred predominantly in right-sided patient-derived colorectal cancer organoids, which were associated with increased chromatin accessibility. Re-compaction of chromatin by methylstat, a histone demethylase inhibitor, resulted in reduced growth selectively in subcutaneously grown tumors derived from right-sided cancers. Using mouse intestinal organoids, we confirmed that Suv4-20h2-mediated H4K20me3 is required for maintaining heterochromatin compaction and to prevent R-loop formation. Cross-species comparison of Suv4-20h2-depleted murine organoids with right-sided colorectal cancer organoids revealed a large overlap of gene signatures involved in chromatin silencing, DNA methylation, and stemness/Wnt signaling. CONCLUSIONS: Loss of Suv4-20h2-mediated H4K20me3 drives right-sided colorectal tumorigenesis through an epigenetically controlled mechanism of chromatin compaction. Our findings unravel a conceptually novel approach for subtype-specific therapy of this aggressive form of colorectal cancer.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression
- Date Crossref
- 01/02/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Goethe University Frankfurt Institute for Tumor Biology and Experimental Therapy pays non établi dans la noticeUniversité ou école supérieure
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Institute of Clinical Cancer Research pays non établi dans la noticeStructure de recherche
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Frankfurt Cancer Institute pays non établi dans la noticeOrganisation à but non lucratif
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Max Planck Institute for Heart and Lung Research Department of Cardiac Development and Remodeling pays non établi dans la noticeStructure de recherche
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German Cancer Research Center Division of Cancer Epigenomics pays non établi dans la noticeStructure de recherche
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Heidelberg University pays non établi dans la noticeUniversité ou école supérieure
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University Hospital Ulm pays non établi dans la noticeÉtablissement de santé
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Johannes Gutenberg University Mainz pays non établi dans la noticeUniversité ou école supérieure
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University Medical Center of the Johannes Gutenberg University Mainz Department of Hematology pays non établi dans la noticeÉtablissement de santé
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Institute for Tumor Biology and Experimental Therapy pays non établi dans la noticeStructure de recherche
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Ulm University Hospital Department of Internal Medicine I pays non établi dans la noticeUniversité ou école supérieure
Institute for Tumor Biology and Experimental Therapy — Goethe University Frankfurt, Institute of Clinical Cancer Research et Frankfurt Cancer Institute, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.