纤维板层肝细胞癌异常增强子活性热点揭示候选致癌途径和治疗弱点。
Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities.
机构信息
Curriculum in Genetics & Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
出版信息
Cell Rep. 2020 Apr 14;31(2):107509. doi: 10.1016/j.celrep.2020.03.073.
Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the chromatin regulatory landscape and the genes most critical for tumor cell survival remain unclear. Here, we use chromatin run-on sequencing to discover ∼7,000 enhancers and 141 enhancer hotspots activated in FLC relative to nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also define the genes most strongly associated with hotspots of FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduce cell viability and/or significantly enhance the effect of the MEK inhibitor cobimetinib. These findings highlight molecular targets for drug development, as well as drug combination approaches.
纤维板层样肝细胞癌（FLC）是一种罕见的、难以治疗的肝癌，它不成比例地影响年轻人。尽管 FLC 肿瘤表现出独特的基因表达谱，但染色质调控景观和对肿瘤细胞存活最重要的基因仍不清楚。在这里，我们使用染色质运行测序来发现与非恶性肝脏相比，FLC 中约有 7000 个增强子和 141 个增强子热点被激活。生物信息学分析揭示了异常的 ERK/MEK 信号和候选主转录调节因子。我们还定义了与 FLC 增强子活性热点最密切相关的基因，包括 CA12 和 SLC16A14。用 CA12 或 SLC16A14 的抑制剂治疗 FLC 细胞模型可独立降低细胞活力，或显著增强 MEK 抑制剂 cobimetinib 的作用。这些发现突出了药物开发的分子靶点，以及药物联合治疗方法。
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