Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Derqui-Pilar, Argentina.
Center for Liver Diseases, Pittsburgh Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
J Hepatol. 2019 Jul;71(1):78-90. doi: 10.1016/j.jhep.2019.03.007. Epub 2019 Mar 15.
BACKGROUND & AIMS: A causal link has recently been established between epigenetic alterations and hepatocarcinogenesis, indicating that epigenetic inhibition may have therapeutic potential. We aimed to identify and target epigenetic modifiers that show molecular alterations in hepatocellular carcinoma (HCC).
We studied the molecular-clinical correlations of epigenetic modifiers including bromodomains, histone acetyltransferases, lysine methyltransferases and lysine demethylases in HCC using The Cancer Genome Atlas (TCGA) data of 365 patients with HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA sequencing analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylase (JmjC) inhibitors.
Genetic alterations, aberrant expression, and correlation between tumor expression and poor patient prognosis of epigenetic enzymes are common events in HCC. Epigenetic inhibitors that target bromodomain (JQ-1), lysine methyltransferases (BIX-1294 and LLY-507) and JmjC lysine demethylases (JIB-04, GSK-J4 and SD-70) reduce HCC aggressiveness. The pan-JmjC inhibitor JIB-04 had a potent antitumor effect in tumor bearing mice. HCC cells treated with JmjC inhibitors showed overlapping changes in expression programs related with inhibition of cell proliferation and induction of cell death. JmjC inhibition reverses an aggressive HCC gene expression program that is also altered in patients with HCC. Several genes downregulated by JmjC inhibitors are highly expressed in tumor vs. non-tumor parenchyma, and their high expression correlates with a poor prognosis. We identified and validated a 4-gene expression prognostic signature consisting of CENPA, KIF20A, PLK1, and NCAPG.
The epigenetic alterations identified in HCC can be used to predict prognosis and to define a subgroup of high-risk patients that would potentially benefit from JmjC inhibitor therapy.
In this study, we found that mutations and changes in expression of epigenetic modifiers are common events in human hepatocellular carcinoma, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibition of Jumonji enzymes. This inhibition blocks hepatocellular carcinoma progression, providing a novel potential therapeutic strategy.
最近已经确立了表观遗传改变与肝癌发生之间的因果关系，表明表观遗传抑制可能具有治疗潜力。我们旨在鉴定和靶向在肝细胞癌（HCC）中显示分子改变的表观遗传修饰物。
我们使用来自 365 例 HCC 患者的癌症基因组图谱（TCGA）数据，研究了包括溴结构域、组蛋白乙酰转移酶、赖氨酸甲基转移酶和赖氨酸去甲基酶在内的表观遗传修饰物的分子临床相关性。在体外和体内评估了表观遗传抑制剂的治疗潜力。使用 RNA 测序分析及其与 TCGA 数据集的表达和临床数据的相关性，鉴定了由 Jumonji 赖氨酸去甲基酶（JmjC）抑制剂归一化的表达程序。
遗传改变、异常表达以及肿瘤表达与患者预后不良之间的相关性是 HCC 中的常见事件。靶向溴结构域（JQ-1）、赖氨酸甲基转移酶（BIX-1294 和 LLY-507）和 JmjC 赖氨酸去甲基酶（JIB-04、GSK-J4 和 SD-70）的表观遗传抑制剂可降低 HCC 的侵袭性。泛 JmjC 抑制剂 JIB-04 在荷瘤小鼠中具有很强的抗肿瘤作用。用 JmjC 抑制剂处理的 HCC 细胞表现出与细胞增殖抑制和细胞死亡诱导相关的重叠表达程序变化。JmjC 抑制逆转了 HCC 基因表达程序，该程序在 HCC 患者中也发生了改变。JmjC 抑制剂下调的几个基因在肿瘤与非肿瘤实质中高表达，其高表达与预后不良相关。我们鉴定并验证了一个由 CENPA、KIF20A、PLK1 和 NCAPG 组成的 4 基因表达预后签名。
在 HCC 中鉴定的表观遗传改变可用于预测预后，并定义潜在受益于 JmjC 抑制剂治疗的高危患者亚组。
在这项研究中，我们发现表观遗传修饰物的突变和表达变化是人类肝细胞癌中的常见事件，导致侵袭性基因表达程序和不良的临床预后。通过组蛋白去甲基酶的药理学抑制可以逆转转录程序。这种抑制阻止了肝细胞癌的进展，为新的潜在治疗策略提供了依据。
