Xue Lin1, Jan Stenvang2, Mads Heilskov Rasmussen3, Shida Zhu4, Niels Frank Jensen5, Line S Tarpgaard6, Guangxia Yang7, Kirstine Belling8, Claus Lindbjerg Andersen9, Jian Li10,11,12, Lars Bolund13,14, Nils Brünner15. 1. Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. xue.lin@biomed.au.dk. 2. Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. stenvang@sund.ku.dk. 3. Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, DK-8200, Aarhus N, Denmark. mads.heilskov@ki.au.dk. 4. BGI (Beijing Genomics Institute), Shenzhen, 518083, China. zhushida@genomics.org.cn. 5. Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. nfj@sund.ku.dk. 6. Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense C, Denmark. line.tarpgaard@rsyd.dk. 7. BGI (Beijing Genomics Institute), Shenzhen, 518083, China. yanggx@genomics.cn. 8. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, 2800, Lyngby, Denmark. belling@cbs.dtu.dk. 9. Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, DK-8200, Aarhus N, Denmark. cla@ki.au.dk. 10. Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. jili@biomed.au.dk. 11. BGI (Beijing Genomics Institute), Shenzhen, 518083, China. jili@biomed.au.dk. 12. The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China. jili@biomed.au.dk. 13. Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. bolund@biomed.au.dk. 14. BGI (Beijing Genomics Institute), Shenzhen, 518083, China. bolund@biomed.au.dk. 15. Department of Veterinary Disease Biology, Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Copenhagen University, Strandboulevarden 49, Copenhagen, Denmark. nbr@sund.ku.dk.
Abstract
BACKGROUND: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. RESULTS: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. CONCLUSION: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.
BACKGROUND:Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. RESULTS: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. CONCLUSION: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.
Authors: Bradley J Wagstaff; Emily N Kroutter; Rebecca S Derbes; Victoria P Belancio; Astrid M Roy-Engel Journal: Mol Biol Evol Date: 2012-08-23 Impact factor: 16.240
Authors: Ludmila A Alekseeva; Nadezhda L Mironova; Evgenyi V Brenner; Alexander M Kurilshikov; Olga A Patutina; Marina A Zenkova Journal: PLoS One Date: 2017-02-21 Impact factor: 3.240
Authors: Sophie E B Ambjørner; Michael Wiese; Sebastian Christoph Köhler; Joen Svindt; Xamuel Loft Lund; Michael Gajhede; Lasse Saaby; Birger Brodin; Steffen Rump; Henning Weigt; Nils Brünner; Jan Stenvang Journal: Cells Date: 2020-03-04 Impact factor: 6.600