Cytostatic drug treatment causes seeding of gene promoter methylation.
Epigenetic changes in multiple genes are emerging as an important mechanism for tumour cells to acquire resistance to chemotherapy. In the present work, we test the hypothesis that epigenetic organisation in cancer cells can be affected by cytostatic drugs. Colorectal cancer cells were cultured for several weeks in the presence of 6-thioguanine. Bisulphite sequencing of the CpG-rich promoter regions of two expressed genes showed a significantly increased frequency of methylated CpG sites in drug-treated cells, as compared with controls: 4.7% and 1.7%, respectively, for the HPRT gene; and 11.1% and 8.2% for CDX1. Essentially, all of the increase for the CDX1 gene was in a four CpG sub-region previously found to correlate with gene activity (P=0.006). This pattern of sparse promoter methylation fits with a recently proposed 'seeding' two-step mechanism leading up to gene inactivation in cancer cells. Taken together, our findings suggest activation in cancer cells of an epigenetic process enabling a tumour to generate drug-resistant variant cells.
Bredberg
Anders
A
Cancer Research UK Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Bodmer
Walter
W
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008214:Lymphocytes; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013447:Sulfites / Q000378:metabolism; D013866:Thioguanine / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; C491273:CDX1 protein, human; D018398:Homeodomain Proteins; D013447:Sulfites; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; C042345:hydrogen sulfite