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Irinotecan Inactivation Is Modulated by Epigenetic Silencing of UGT1A1 in Colon Cancer

Authors' Affiliations: ¹ Canada Research Chair in Pharmacogenomics and ² Oncology and Molecular Endocrinology Research Center, Centre Hospitalier de l'Université Laval Research Center, Faculty of Pharmacy and ³ Department of Pathology, Hôtel-Dieu de Québec, Laval University, Quebec, Canada

Requests for reprints: Chantal Guillemette, Canada Research Chair in Pharmacogenomics, Pharmacogenomics Laboratory, Centre de Recherche du Centre Hospitalier de l'Université Laval Research Center, T3-67, 2705 Boul. Laurier, T3-48 Quebec, Canada G1V 4G2. Phone: 418-654-2296; Fax: 418-654-2761; E-mail: chantal.guillemette{at}crchul.ulaval.ca.

Purpose: Irinotecan is used in the first-line treatment of metastatic colorectal cancer. The UGT1A1-metabolizing enzyme, expressed in liver and colon, is primarily involved in the inactivation of its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Herein, we explored the role of DNA methylation in the silencing of UGT1A1 gene expression in colon cancer and its influence on cellular SN-38 detoxification.

Experimental Design and Results: UGT1A1 mRNA was repressed in most primary tumors (41 of 50; 82%) and in three colon cancer cell lines (HCT-116, HCT-15, and COLO-320DM). Bisulfite sequencing of the UGT1A1 gene revealed the aberrant methylation of specific CpG islands in UGT1A1-negative cells. Conversely, hypomethylation was observed in HT-29, HT-115, and LOVO cells that overexpress UGT1A1. Direct methylation of the UGT1A1 promoter resulted in the complete repression of transcriptional activity. Treatment with demethylating and histone deacetylase inhibitor agents had the capacity to reverse aberrant hypermethylation and to restore UGT1A1 expression in hypermethylated UGT1A1-negative cells but not in hypomethylated cells. Loss of UGT1A1 methylation was further associated with an increase in UGT1A1 protein content and with an enhanced inactivation of SN-38 by 300% in HCT-116 cells.

Conclusions: We conclude that DNA methylation represses UGT1A1 expression in colon cancer and that this process may contribute to the level of tumoral inactivation of the anticancer agent SN-38 and potentially influence clinical response.