组蛋白赖氨酸甲基转移酶SMYD3通过h3k4me3介导的HMGA2转录促进口腔鳞状细胞癌的发生。

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-05-26 DOI:10.1186/s13148-023-01506-9
Zongcheng Yang, Fen Liu, Zongkai Li, Nianping Liu, Xinfeng Yao, Yu Zhou, Liyu Zhang, Pan Jiang, Honghong Liu, Lingming Kong, Chuandong Lang, Xin Xu, Jihui Jia, Takahito Nakajima, Wenchao Gu, Lixin Zheng, Zhihong Zhang
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引用次数: 1

摘要

背景:表观遗传失调是口腔鳞状细胞癌(OSCC)发生的关键。SET和MYND结构域蛋白3 (SMYD3)是一种组蛋白赖氨酸甲基转移酶,与基因转录调控和肿瘤发生有关。然而,SMYD3在OSCC发生中的作用尚不完全清楚。本研究利用生物信息学方法和验证试验研究了smyd3介导的OSCC肿瘤发生的生物学功能和机制,旨在为OSCC靶向治疗的开发提供信息。结果:通过机器学习方法筛选出429个染色质调节因子,发现SMYD3的异常表达与OSCC的形成和不良预后密切相关。单细胞和组织数据分析表明,SMYD3上调与OSCC侵袭性临床病理特征显著相关。拷贝数和DNA甲基化模式的改变可能导致SMYD3过表达。功能实验结果表明,SMYD3在体外促进癌细胞的干细胞性和增殖,在体内促进肿瘤生长。观察到SMYD3与高迁移率组at - hook 2 (HMGA2)启动子结合,相应位点组蛋白H3赖氨酸4三甲基化升高负责HMGA2的反激活。SMYD3也与OSCC样品中的HMGA2表达呈正相关。此外,用SMYD3化学抑制剂BCI-121治疗具有抗肿瘤作用。结论:组蛋白甲基转移酶活性和SMYD3的转录增强功能在肿瘤发生中至关重要,SMYD3- hmga2是OSCC的潜在治疗靶点。
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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Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription.

Background: Epigenetic dysregulation is essential to the tumorigenesis of oral squamous cell carcinoma (OSCC). SET and MYND domain-containing protein 3 (SMYD3), a histone lysine methyltransferase, is implicated in gene transcription regulation and tumor development. However, the roles of SMYD3 in OSCC initiation are not fully understood. The present study investigated the biological functions and mechanisms involved in the SMYD3-mediated tumorigenesis of OSCC utilizing bioinformatic approaches and validation assays with the aim of informing the development of targeted therapies for OSCC.

Results: 429 chromatin regulators were screened by a machine learning approach and aberrant expression of SMYD3 was found to be closely associated with OSCC formation and poor prognosis. Data profiling of single-cell and tissue demonstrated that upregulated SMYD3 significantly correlated with aggressive clinicopathological features of OSCC. Alterations in copy number and DNA methylation patterns may contribute to SMYD3 overexpression. Functional experimental results suggested that SMYD3 enhanced cancer cell stemness and proliferation in vitro and tumor growth in vivo. SMYD3 was observed to bind to the High Mobility Group AT-Hook 2 (HMGA2) promoter and elevated tri-methylation of histone H3 lysine 4 at the corresponding site was responsible for transactivating HMGA2. SMYD3 also was positively linked to HMGA2 expression in OSCC samples. Furthermore, treatment with the SMYD3 chemical inhibitor BCI-121 exerted anti-tumor effects.

Conclusions: Histone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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