最近已经建立了表观遗传改变和肝癌之间的因果关系。表明表观遗传抑制可能具有治疗潜力。我们的目的是鉴定和靶向显示肝细胞癌(HCC)分子改变的表观遗传修饰剂。
我们研究了表观遗传修饰因子的分子-临床相关性,包括溴结构域,组蛋白乙酰转移酶,使用365例HCC患者的癌症基因组图谱(TCGA)数据在HCC中的赖氨酸甲基转移酶和赖氨酸去甲基酶。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数据集中的表达和临床数据的相关性来鉴定由Jumonji赖氨酸去甲基酶(JmjC)抑制剂标准化的表达程序。
遗传改变,异常表达,表观遗传学酶的表达与肝癌患者预后不良之间存在相关性。靶向溴结构域(JQ-1)的表观遗传抑制剂,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)可降低HCC的侵袭性。pan-JmjC抑制剂JIB-04在荷瘤小鼠中具有有效的抗肿瘤作用。用JmjC抑制剂处理的HCC细胞显示与抑制细胞增殖和诱导细胞死亡相关的表达程序的重叠变化。JmjC抑制逆转了在HCC患者中也改变的侵袭性HCC基因表达程序。JmjC抑制剂下调的几个基因在肿瘤中高表达。非肿瘤实质,它们的高表达与不良预后相关。我们鉴定并验证了由CENPA组成的4基因表达预后特征,KIF20A,PLK1和NCAPG。
在HCC中鉴定的表观遗传学改变可用于预测预后和定义可能从JmjC抑制剂治疗中受益的高危患者亚组。
在这项研究中,我们发现表观遗传修饰因子的突变和表达变化是人类肝细胞癌的常见事件,导致积极的基因表达程序和不良的临床预后。转录程序可以通过Jumonji酶的药理学抑制来逆转。这种抑制作用阻止了肝细胞癌的进展,提供一种新的潜在治疗策略。
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.