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

Abstract

BackgroundIrinotecan (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.ResultsWe 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1552-y) contains supplementary material, which is available to authorized users.

The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP

“…These resistant cell lines were established by exposing chemotherapy-sensitive cells to gradually increasing concentrations of chemotherapy over a period of 8-10 months [25]. We thoroughly characterized these drug-resistant cell lines to identify important drug resistance mechanisms [25][26][27][28][29][30]. In accordance with several other studies with in vitro model systems [31], we found that BCRP overexpression was a key player of resistance to SN-38 [25].…”

Alteration of the exDNA profile in blood serum of LLC-bearing mice under the decrease of tumour invasion potential by bovine pancreatic DNase I treatment

“…So the insertion of full-length SVA (SINE-VNTR-Alu human retrotransposons) into intron 8 of the caspase 8 ( CASP8 ) gene is associated with cutaneous basal cell carcinoma and breast cancer [ 70 ]. To date, the most commonly used markers for human carcinogenesis are ALU repeats [ 71 – 73 ], which were shown to be significantly over-presented in breast cancer and colorectal cancer patients [ 48 , 49 , 74 , 75 ]. Repeatedly, it was shown that the development of various types of cancer is accompanied by an increase in the abundance of SINE and LINE elements in circulating exDNA [ 74 , 76 – 78 ].…”

Diet‐Induced Paternal Obesity Impairs Cognitive Function in Offspring by Mediating Epigenetic Modifications in Spermatozoa

“…Genomic DNA was extracted from sperm samples, and bisulfite conversion was performed using the EZ DNA Methylation‐Gold Kit (Zymo Research; D5006). RRBS library construction and sequencing were performed at Genergy Bio (Shanghai, China) as described previously .…”