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An Integrated Genomic and Epigenomic Approach Predicts Therapeutic Response to Zebularine in Human Liver Cancer

Authors
 Jesper B. Andersen  ;  Valentina M. Factor  ;  Jens U. Marquardt  ;  Chiara Raggi  ;  Yun-Han Lee  ;  Daekwan Seo  ;  Elizabeth A. Conner  ;  Snorri S. Thorgeirsson 
Citation
 SCIENCE TRANSLATIONAL MEDICINE, Vol.2(54) : 54-77, 2010 
Journal Title
SCIENCE TRANSLATIONAL MEDICINE
ISSN
 1946-6234 
Issue Date
2010
MeSH
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/drug therapy* ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; CpG Islands ; Cytidine/analogs & derivatives* ; Cytidine/therapeutic use ; DNA Methylation ; Epigenesis, Genetic* ; Gene Expression Profiling ; Genome, Human* ; Humans ; Liver Neoplasms/drug therapy* ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Mice ; Transplantation, Heterologous
Abstract
Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome
Files in This Item:
T201006076.pdf Download
DOI
10.1126/scitranslmed.3001338
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Lee, Yun Han(이윤한)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103301
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