An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer

Jesper B. Andersen, Valentina M. Factor, Jens U. Marquardt, Chiara Raggi, Yun Han Lee, Daekwan Seo, Elizabeth A. Conner, Snorri S. Thorgeirsson

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number54ra77
JournalScience Translational Medicine
Volume2
Issue number54
DOIs
Publication statusPublished - Oct 20 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Andersen, J. B., Factor, V. M., Marquardt, J. U., Raggi, C., Lee, Y. H., Seo, D., Conner, E. A., & Thorgeirsson, S. S. (2010). An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer. Science Translational Medicine, 2(54), [54ra77]. https://doi.org/10.1126/scitranslmed.3001338