An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer.
An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer.
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DOI：
10.1126/scitranslmed.3001338
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发表时间：
2010-10-20
影响因子：
17.1
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
--
作者：
Andersen JB;Factor VM;Marquardt JU;Raggi C;Lee YH;Seo D;Conner EA;Thorgeirsson SS
表观基因组变化，例如异常的高甲基化和随后的非典型基因沉默是人类癌症的特征。在这里，我们报告了泽布林（一种有效的 DNA 甲基化抑制剂）在人类肝癌中引起的表观基因组调节的全面特征。通过转录组和表观基因组分析，我们确定了 zebularine 特征，该特征将肝癌细胞系分为具有不同药物反应的两种主要亚型。在药物敏感细胞系中，zebularine 会抑制增殖并增加细胞凋亡，而耐药细胞系则与致癌网络（例如 E2F1、MYC 和 TNF）上调有关，从而在体外和临床前小鼠模型中驱动肝癌生长。在异种移植小鼠模型中对基于 zebularine 的疗法进行的评估表明，对由 zebularine 敏感但不是 zebularine 耐药的肝癌细胞建立的肿瘤具有有效的治疗作用，从而提高存活率并减少肺转移。 zebularine 基因表达和去甲基化反应特征的整合根据 HCC 患者的生存和疾病复发来区分患者，并确定了贫困幸存者中可能受益于针对癌症表观基因组的治疗药物的患者亚类。
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 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 were associated with upregulation of oncogenic networks (e.g. E2F1, MYC, and TNF) driving 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 zebularine gene expression and demethylation response signatures differentiated patients with HCC according to their survival and disease recurrence and identified a subclass of patients within the poor survivors likely to benefit from therapeutic agents that target the cancer epigenome.
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