Thioredoxin-interacting protein-activated intracellular potassium deprivation mediates the anti-tumour effect of a novel histone acetylation inhibitor HL23, a fangchinoline derivative, in human hepatocellular carcinoma,Journal of Advanced Research

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Thioredoxin-interacting protein-activated intracellular potassium deprivation mediates the anti-tumour effect of a novel histone acetylation inhibitor HL23, a fangchinoline derivative, in human hepatocellular carcinoma
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-11-06 , DOI: 10.1016/j.jare.2022.10.017
Yuanjun Lu ₁ , Yazhou Liu ₂ , Junjie Lan ₃ , Yau-Tuen Chan ₁ , Zixin Feng ₁ , Lan Huang ₁ , Ning Wang ₁ , Weidong Pan ₃ , Yibin Feng ₁

Affiliation

Introduction

Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC). Although multiple pharmacological HDAC inhibitors (HDACis) have been developed, none is available in human HCC.

Objectives

To investigate the pharmacological effects of a fangchinoline derivative HL23, as a novel HDACi and its molecular mechanisms through TXNIP-mediated potassium deprivation in HCC.

Methods

Both in vitro assays and orthotopic HCC mouse models were used to investigate the effects of HL23 in this study. The inhibitory activity of HL23 on HDACs was evaluated by in silico studies and cellular assays. Chromatin immunoprecipitation (ChIP) was conducted to confirm the regulation of HL23 on acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic analysis were conducted to identify the regulatory mechanisms of HL23. The clinical significance of TXNIP and HDACs was evaluated by analysing publicly available database.

Results

HL23 exerted compatible HDACs inhibition potency as Vorinostat (SAHA) while had superior anti-HCC effects than SAHA and sorafenib. Both in vitro and in vivo studies showed HL23 significantly suppressed HCC progression and metastasis. HL23 significantly upregulated TXNIP expression via regulating acetylation mark (H3K9ac) at TXNIP promoter. TXNIP was responsible for anti-HCC activity of HL23 through mediating potassium channel activity. HDAC1 was predicted to be the target of HL23 and HDAC1^lowTXNIP^high could jointly predict promising survival outcome of patients with HCC. Combination treatment with HL23 and sorafenib could significantly enhance sorafenib efficacy.

Conclusion

Our study identified HL23 as a novel HDACi through enhancing acetylation at TXNIP promoter to trigger TXNIP-dependent potassium deprivation and enhance sorafenib efficacy in HCC treatment.

中文翻译：

硫氧还蛋白相互作用蛋白激活的细胞内缺钾介导新型组蛋白乙酰化抑制剂 HL23（一种防己诺林衍生物）在人肝细胞癌中的抗肿瘤作用

介绍

过度激活的组蛋白脱乙酰酶 (HDAC) 作为基因转录的表观遗传抑制因子，经常在人类肝细胞癌 (HCC) 中观察到。尽管已经开发出多种药理学 HDAC 抑制剂 (HDACis)，但尚无一种可用于人类 HCC。

目标

研究防己诺林衍生物HL23作为一种新型 HDACi 的药理作用及其通过 TXNIP 介导的缺钾治疗 HCC 的分子机制。

方法

本研究中使用体外测定和原位 HCC 小鼠模型来研究HL23的作用。通过计算机研究和细胞测定评估了HL23对 HDAC的抑制活性。进行染色质免疫沉淀 (ChIP) 以确认HL23对 TXNIP 启动子乙酰化标记的调节。进行全基因组转录组分析和生物信息学分析，以确定HL23的调控机制。通过分析公开数据库评估 TXNIP 和 HDAC 的临床意义。

结果

HL23发挥与伏立诺他 (SAHA) 相容的 HDAC 抑制效力，同时比 SAHA 和索拉非尼具有更好的抗 HCC 作用。体外和体内研究均表明HL23显着抑制 HCC 进展和转移。HL23通过调节 TXNIP 启动子处的乙酰化标记 (H3K9ac) 显着上调 TXNIP 表达。TXNIP通过介导钾通道活性负责HL23的抗 HCC 活性。HDAC1 被预测为HL23的靶标，HDAC1^低、TXNIP^高可以共同预测 HCC 患者有希望的生存结果。HL23与索拉非尼联合治疗可显着增强索拉非尼疗效。