The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer

Xue Lin, Jan Stenvang, Mads Heilskov Rasmussen, Shida Zhu, Niels Frank Jensen, Line S Tarpgaard, Guangxia Yang, Kirstine Belling, Claus Lindbjerg Andersen, Jian Li, Lars Bolund, Nils Brünner

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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.

Original languageEnglish
Article number404
JournalBMC Genomics
Volume16
Number of pages17
ISSN1471-2164
DOIs
Publication statusPublished - 22. May 2015

Keywords

  • Alu
  • Cell fate dynamics
  • Colorectal cancer
  • DNA methylation
  • Diversity
  • SN38 and oxaliplatin resistance
  • HCT116 Cells
  • Humans
  • Drug Resistance, Neoplasm
  • Organoplatinum Compounds/pharmacology
  • Colorectal Neoplasms/drug therapy
  • HT29 Cells
  • SOX Transcription Factors/genetics
  • Irinotecan
  • Antineoplastic Agents/pharmacology
  • DNA Methylation
  • Oxaliplatin
  • Alu Elements/drug effects
  • Camptothecin/analogs & derivatives

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