title: Identification of a potent epigenetic biomarker for resistance to camptothecin             and poor outcome to irinotecan-based chemotherapy in colon cancer.
abstract: Drug resistance remains a major obstacle to successful cancer treatment.             Genome-wide comprehensive analysis identified a novel gene, glucocorticoid-induced             protein-coding gene (DEXI), which was frequently methylated in colorectal (CRC;             36 of 73 patients; 49%) and gastric (28 of 89 patients; 31%) cancer patients.             Here, we show that DEXI methylation is implicated in mechanisms facilitating resistance             to camptothecin (CPT) via inhibition of apoptosis. Silencing of DEXI by siRNA             significantly reduced CPT-induced apoptosis in a fibroblast cell line (1/6-fold;             p<0.01) originally expressing endogenous DEXI. Restored expression of DEXI             by 5-aza-2'-deoxycytidine (DAC) significantly enhanced susceptibility to CPT (3-fold;             p<0.01) in a colon cancer cell line originally suppressing endogenous DEXI             due to almost complete methylation. Exogenous induction of DEXI confirmed that             DEXI per se contributed to enhanced susceptibility to CPT. 5-Fluorouracil (5-FU)             did not exhibit these synergistic effects by DEXI restoration. Further, to estimate             the clinical usefulness of DEXI methylation status as biomarker for drug resistance             to irinotecan (CPT-11), 16 CRC patients who underwent FOLFIRI (5-FU + CPT-11)             therapy because they were refractory to FOLFOX (5-FU + oxaliplatin) were analyzed.             Significantly poor response and outcome were observed in 8 CRC patients harboring             DEXI methylation. In 8 CRC patients harboring DEXI methylation disease control             rate, progression-free survival and overall survival were 25.0%, 2 and 11.8 months,             respectively, whereas in 8 CRC patients without DEXI methylation they were 62.5%,             5.3 and 15 months, respectively (p<0.01). These significant differences were             not observed in patients undergoing treatment with FOLFOX. In conclusion, silencing             of DEXI leads to resistance, but restored expression enhances susceptibility to             CPT in vitro and DEXI methylation results in poor response and outcome to CPT-11-based             chemotherapy, suggesting that DEXI is a potent therapeutic target and an epigenetic             biomarker for the selection of patients more likely to benefit from CPT-11-based             chemotherapy.
authors: First Department of Surgery, Hamamatsu University School of Medicine,                     1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors: Yuichiro
authors: Y
authors: Miyaki
authors: Koichi
authors: K
authors: Suzuki
authors: Kei
authors: K
authors: Koizumi
authors: Takaharu
authors: T
authors: Kato
authors: Masaaki
authors: M
authors: Saito
authors: Hidenori
authors: H
authors: Kamiyama
authors: Takafumi
authors: T
authors: Maeda
authors: Kiyoshi
authors: K
authors: Shibata
authors: Norihiko
authors: N
authors: Shiya
authors: Fumio
authors: F
authors: Konishi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D018938:Caco-2 Cells; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C433368:DEXI protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin