Abrogating K458 acetylation enhances hepatocyte nuclear factor 4α (HNF4α)-induced differentiation therapy for hepatocellular carcinoma

IF 2.3 3区医学 Q3 GASTROENTEROLOGY & HEPATOLOGY

Journal of Digestive Diseases Pub Date : 2024-06-04 DOI:10.1111/1751-2980.13272

Fang Liu, Yu Peng, Hui Qian, Meng Chao Xiao, Chen Hong Ding, Xin Zhang, Wei Fen Xie

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引用次数: 0

Abstract

Objectives

In this study we aimed to assess the impact of acetylation of hepatocyte nuclear factor 4α (HNF4α) on lysine 458 on the differentiation therapy of hepatocellular carcinoma (HCC).

Methods

Periodic acid-Schiff (PAS) staining, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and senescence-associated β-galactosidase (SA-β-gal) activity analysis were performed to assess the differentiation of HCC cells. HNF4α protein was detected by western blot and immunohistochemistry (IHC). The effects of HNF4α-K458 acetylation on HCC malignancy were evaluated in HCC cell lines, a Huh-7 xenograft mouse model, and an orthotopic model. The differential expression genes in Huh-7 xenograft tumors were screened by RNA-sequencing analysis.

Results

K458R significantly enhanced the inhibitory effect of HNF4α on the malignancy of HCC cells, whereas K458Q reduced the inhibitory effects of HNF4α. Moreover, K458R promoted, while K458Q decreased, HNF4α-induced HCC cell differentiation. K458R stabilized HNF4α, while K458Q accelerated the degradation of HNF4α via the ubiquitin proteasome system. K458R also enhanced the ability of HNF4α to inhibit cell growth of HCC in the Huh-7 xenograft mouse model and the orthotopic model. RNA-sequencing analysis revealed that inhibiting K458 acetylation enhanced the transcriptional activity of HNF4α without altering the transcriptome induced by HNF4α in HCC.

Conclusion

Our data revealed that inhibiting K458 acetylation of HNF4α might provide a more promising candidate for differential therapy of HCC.

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废除 K458 乙酰化可增强肝细胞核因子 4α (HNF4α) 诱导的肝细胞癌分化疗法

目的本研究旨在评估肝细胞核因子 4α (HNF4α) 赖氨酸 458 上的乙酰化对肝细胞癌 (HCC) 分化治疗的影响。方法对 HCC 细胞进行周期性酸-Schiff（PAS）染色、Dil-乙酰化低密度脂蛋白（Dil-Ac-LDL）摄取和衰老相关β-半乳糖苷酶（SA-β-gal）活性分析，以评估 HCC 细胞的分化情况。HNF4α蛋白通过Western印迹和免疫组织化学（IHC）进行检测。在HCC细胞系、Huh-7异种移植小鼠模型和正位模型中评估了HNF4α-K458乙酰化对HCC恶性程度的影响。通过 RNA 序列分析筛选了 Huh-7 异种移植瘤中的差异表达基因。结果 K458R明显增强了HNF4α对HCC细胞恶性程度的抑制作用，而K458Q则降低了HNF4α的抑制作用。此外，K458R能促进而K458Q能降低HNF4α诱导的HCC细胞分化。K458R 稳定了 HNF4α，而 K458Q 则加速了 HNF4α 通过泛素蛋白酶体系统的降解。K458R还增强了HNF4α在Huh-7异种移植小鼠模型和正位模型中抑制HCC细胞生长的能力。RNA 序列分析表明，抑制 K458 乙酰化可增强 HNF4α 的转录活性，但不会改变 HNF4α 在 HCC 中诱导的转录组。结论我们的数据显示，抑制 HNF4α 的 K458 乙酰化可能为 HCC 的差异化治疗提供更有前景的候选方案。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Digestive Diseases 医学-胃肠肝病学

CiteScore

5.40

自引率

2.90%

发文量

审稿时长

6-12 weeks

期刊介绍： The Journal of Digestive Diseases is the official English-language journal of the Chinese Society of Gastroenterology. The journal is published twelve times per year and includes peer-reviewed original papers, review articles and commentaries concerned with research relating to the esophagus, stomach, small intestine, colon, liver, biliary tract and pancreas.