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

TY - JOUR

T1 - An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer

AU - Andersen, Jesper Bøje

AU - Factor, Valentina M

AU - Marquardt, Jens U

AU - Raggi, Chiara

AU - Lee, Yun-Han

AU - Seo, Daekwan

AU - Conner, Elizabeth A

AU - Thorgeirsson, Snorri S

PY - 2010/10/20

Y1 - 2010/10/20

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Carcinoma, Hepatocellular

KW - Cell Line, Tumor

KW - CpG Islands

KW - Cytidine

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Gene Expression Profiling

KW - Genome, Human

KW - Humans

KW - Liver Neoplasms

KW - Mice

KW - Transplantation, Heterologous

U2 - 10.1126/scitranslmed.3001338

DO - 10.1126/scitranslmed.3001338

M3 - Journal article

C2 - 20962331

SN - 1946-6234

VL - 2

SP - 54ra77

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 54

ER -