Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation
Abstract Background Colorectal cancer (CRC) progression from adenoma to adenocarcinoma is associated with global reduction in 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). DNA hypomethylation continues upon liver metastasis. Here we examine 5hmC changes upon progression to liver metasta...
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2025-04-01
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| Online Access: | https://doi.org/10.1186/s12915-025-02205-y |
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| author | Ben Murcott Floris Honig Dominic Oliver Halliwell Yuan Tian James Lawrence Robson Piotr Manasterski Jennifer Pinnell Thérèse Dix-Peek Santiago Uribe-Lewis Ashraf E. K. Ibrahim Julia Sero David Gurevich Nikolas Nikolaou Adele Murrell |
| author_facet | Ben Murcott Floris Honig Dominic Oliver Halliwell Yuan Tian James Lawrence Robson Piotr Manasterski Jennifer Pinnell Thérèse Dix-Peek Santiago Uribe-Lewis Ashraf E. K. Ibrahim Julia Sero David Gurevich Nikolas Nikolaou Adele Murrell |
| author_sort | Ben Murcott |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) progression from adenoma to adenocarcinoma is associated with global reduction in 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). DNA hypomethylation continues upon liver metastasis. Here we examine 5hmC changes upon progression to liver metastasis. Results 5hmC is increased in metastatic liver tissue relative to the primary colon tumour and expression of TET2 and TET3 is negatively correlated with risk for metastasis in patients with CRC. Genes associated with increased 5-hydroxymethylcytosine show KEGG enrichment for adherens junctions, cytoskeleton and cell migration around a core cadherin (CDH2) network. Overall, the 5-hydroxymethylcyosine profile in the liver metastasis is similar to normal colon appearing to recover at many loci where it was originally present in normal colon and then spreading to adjacent sites. The underlying sequences at the recover and spread regions are enriched for SALL4, ZNF770, ZNF121 and PAX5 transcription factor binding sites. Finally, we show in a zebrafish migration assay using SW480 CRISPR-engineered TET knockout and rescue cells that reduced TET expression leads to a reduced migration frequency. Conclusions Together these results suggest a biphasic trajectory for 5-hydroxymethyation dynamics that has bearing on potential therapeutic interventions aimed at manipulating 5-hydroxymethylcytosine levels. |
| format | Article |
| id | doaj-art-e2158236cb594025bcd0043a83dbd546 |
| institution | DOAJ |
| issn | 1741-7007 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj-art-e2158236cb594025bcd0043a83dbd5462025-08-20T03:18:34ZengBMCBMC Biology1741-70072025-04-0123111910.1186/s12915-025-02205-yColorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulationBen Murcott0Floris Honig1Dominic Oliver Halliwell2Yuan Tian3James Lawrence Robson4Piotr Manasterski5Jennifer Pinnell6Thérèse Dix-Peek7Santiago Uribe-Lewis8Ashraf E. K. Ibrahim9Julia Sero10David Gurevich11Nikolas Nikolaou12Adele Murrell13Department of Life Sciences, University of BathDepartment of Life Sciences, University of BathDepartment of Life Sciences, University of BathDepartment of Life Sciences, University of BathDepartment of Applied Sciences, University of the West of EnglandEdinburgh Cancer Research Centre, Institute of Genetics and Cancer, The University of EdinburghPublic Library of ScienceDepartment of Medicine, Faculty of Health Sciences, University of the WitwatersrandThe Stokes Center for Urology, Royal Surrey Hospital NHS Foundation TrustNorth West Anglia Foundation Trust, Peterborough City Hospital, Bretton GateDepartment of Life Sciences, Centre for Bioengineering & Biomedical Technologies, University of BathDepartment of Life Sciences, Centre for Bioengineering & Biomedical Technologies, University of BathClinical and Biomedical Sciences, Living Systems Institute, University of ExeterDepartment of Life Sciences, Centre for Bioengineering & Biomedical Technologies, Centre for Mathematical Biology, University of BathAbstract Background Colorectal cancer (CRC) progression from adenoma to adenocarcinoma is associated with global reduction in 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). DNA hypomethylation continues upon liver metastasis. Here we examine 5hmC changes upon progression to liver metastasis. Results 5hmC is increased in metastatic liver tissue relative to the primary colon tumour and expression of TET2 and TET3 is negatively correlated with risk for metastasis in patients with CRC. Genes associated with increased 5-hydroxymethylcytosine show KEGG enrichment for adherens junctions, cytoskeleton and cell migration around a core cadherin (CDH2) network. Overall, the 5-hydroxymethylcyosine profile in the liver metastasis is similar to normal colon appearing to recover at many loci where it was originally present in normal colon and then spreading to adjacent sites. The underlying sequences at the recover and spread regions are enriched for SALL4, ZNF770, ZNF121 and PAX5 transcription factor binding sites. Finally, we show in a zebrafish migration assay using SW480 CRISPR-engineered TET knockout and rescue cells that reduced TET expression leads to a reduced migration frequency. Conclusions Together these results suggest a biphasic trajectory for 5-hydroxymethyation dynamics that has bearing on potential therapeutic interventions aimed at manipulating 5-hydroxymethylcytosine levels.https://doi.org/10.1186/s12915-025-02205-y5-HydroxymethylcytosineColorectal cancer progression to metastasisTen-eleven-translocation (TET)EpigeneticsZebrafish assay |
| spellingShingle | Ben Murcott Floris Honig Dominic Oliver Halliwell Yuan Tian James Lawrence Robson Piotr Manasterski Jennifer Pinnell Thérèse Dix-Peek Santiago Uribe-Lewis Ashraf E. K. Ibrahim Julia Sero David Gurevich Nikolas Nikolaou Adele Murrell Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation BMC Biology 5-Hydroxymethylcytosine Colorectal cancer progression to metastasis Ten-eleven-translocation (TET) Epigenetics Zebrafish assay |
| title | Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation |
| title_full | Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation |
| title_fullStr | Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation |
| title_full_unstemmed | Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation |
| title_short | Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation |
| title_sort | colorectal cancer progression to metastasis is associated with dynamic genome wide biphasic 5 hydroxymethylcytosine accumulation |
| topic | 5-Hydroxymethylcytosine Colorectal cancer progression to metastasis Ten-eleven-translocation (TET) Epigenetics Zebrafish assay |
| url | https://doi.org/10.1186/s12915-025-02205-y |
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