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Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression
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 H4...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
W.B. Saunders
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889219/ https://www.ncbi.nlm.nih.gov/pubmed/36402192 http://dx.doi.org/10.1053/j.gastro.2022.10.036 |
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author | Boonsanay, Verawan Mosa, Mohammed H. Looso, Mario Weichenhan, Dieter Ceteci, Fatih Pudelko, Lorenz Lechel, Andre Michel, Christian S. Künne, Carsten Farin, Henner F. Plass, Christoph Greten, Florian R. |
author_facet | Boonsanay, Verawan Mosa, Mohammed H. Looso, Mario Weichenhan, Dieter Ceteci, Fatih Pudelko, Lorenz Lechel, Andre Michel, Christian S. Künne, Carsten Farin, Henner F. Plass, Christoph Greten, Florian R. |
author_sort | Boonsanay, Verawan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9889219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | W.B. Saunders |
record_format | MEDLINE/PubMed |
spelling | pubmed-98892192023-02-02 Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression Boonsanay, Verawan Mosa, Mohammed H. Looso, Mario Weichenhan, Dieter Ceteci, Fatih Pudelko, Lorenz Lechel, Andre Michel, Christian S. Künne, Carsten Farin, Henner F. Plass, Christoph Greten, Florian R. Gastroenterology Original Research 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. W.B. Saunders 2023-02 /pmc/articles/PMC9889219/ /pubmed/36402192 http://dx.doi.org/10.1053/j.gastro.2022.10.036 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Boonsanay, Verawan Mosa, Mohammed H. Looso, Mario Weichenhan, Dieter Ceteci, Fatih Pudelko, Lorenz Lechel, Andre Michel, Christian S. Künne, Carsten Farin, Henner F. Plass, Christoph Greten, Florian R. Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title | Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title_full | Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title_fullStr | Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title_full_unstemmed | Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title_short | Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression |
title_sort | loss of suv420h2-dependent chromatin compaction drives right-sided colon cancer progression |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889219/ https://www.ncbi.nlm.nih.gov/pubmed/36402192 http://dx.doi.org/10.1053/j.gastro.2022.10.036 |
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