组蛋白去乙酰化酶3促进三阴性乳腺癌细胞上皮－间充质转化的作用和机制研究

doi:10.3969/j.issn.1006-7795.2026.04.015

首都医科大学学报 ›› 2026, Vol. 47 ›› Issue (4): 738-753.doi: 10.3969/j.issn.1006-7795.2026.04.015

组蛋白去乙酰化酶3促进三阴性乳腺癌细胞上皮－间充质转化的作用和机制研究

李情^1#，王嗣淇^1#，马天宇²，马枭琪¹，孙雨婷¹，滕旭¹，余和芬¹，张竞尧^2△*，黄蔚^1△*

1. 首都医科大学基础医学院生物化学与分子生物学系，北京 100069；2. 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院/分子肿瘤学国家重点实验室，北京 100021

收稿日期:2026-04-08 修回日期:2026-05-21 出版日期:2026-08-21 发布日期:2026-07-26
通讯作者: 张竞尧, 黄蔚 E-mail:zhangjingyao@pumc.edu.cn； weihuang@ccmu.edu.cn
基金资助:
国家自然科学基金项目（82273403，82504167），中国博士后科学基金项目（2024M760260）。

Effect of HDAC3 on promoting the epithelial-mesenchymal transition in triple-negative breast cancer

Li Qing^1#, Wang Siqi^1#, Ma Tianyu², Ma Xiaoqi¹, Sun Yuting¹, Teng Xu¹, Yu Hefen¹, Zhang Jingyao^2△*, Huang Wei^1△*

1.Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; 2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Received:2026-04-08 Revised:2026-05-21 Online:2026-08-21 Published:2026-07-26
Supported by:
This study was supported by National Natural Science Foundation of China (82273403, 82504167), China Postdoctoral Science Foundation (2024M760260).

摘要/Abstract

摘要： 目的探究组蛋白去乙酰化酶3（histone deacetylase 3，HDAC3）在三阴性乳腺癌（triple-negative breast cancer，TNBC）细胞上皮－间充质转化（epithelial-mesenchymal transition，EMT）中的作用和机制。方法使用基因表达数据库（Gene Expression Omnibus，GEO）、癌症基因图谱（The Cancer Genome Atlas，TCGA）及免疫组织化学染色（immunohistochemistry，IHC）法检测HDAC3在乳腺癌组织中的表达水平；通过Kaplan-Meier Plotter（KM-plotter）在线工具分析HDAC3表达与TNBC患者预后的相关性。构建HDAC3稳定过表达和敲减的TNBC MDA-MB-231、SUM 159细胞系，利用生长曲线、克隆形成实验检测HDAC3对TNBC细胞增殖能力的影响；通过Transwell实验检测其对细胞迁移、侵袭能力的影响；采用Western blotting法检测EMT相关标志物的表达变化。对HDAC3敲减的MDA-MB-231细胞进行转录组测序（RNA sequencing，RNA-seq）分析，筛选差异表达基因并进行KEGG通路富集分析；利用实时荧光定量反转录聚合酶链式反应（reverse transcription-quantitative real-time polymerase chain reaction，RT-qPCR）验证关键差异基因；通过染色质免疫沉淀聚合酶链式反应（chromatin immunoprecipitation polymerase chain reaction，ChIP-PCR）实验验证HDAC3与靶基因启动子的结合情况，结合公共数据库分析HDAC3与靶基因的表达相关性及临床预后价值。结果 HDAC3在乳腺癌组织中呈高表达，且其高表达与TNBC患者总生存期（overall survival，OS）、无复发生存期（recurrence-free survival，RFS）预后不良密切相关。体外功能实验证实，HDAC3过表达可显著促进MDA-MB-231、SUM 159细胞的增殖、迁移和侵袭能力，并下调上皮标志物α-连环蛋白、γ-连环蛋白表达，上调间充质标志物纤连蛋白、波形蛋白表达，促进TNBC EMT；敲减HDAC3则得到相反结果。RNA-seq分析显示，敲减HDAC3后共筛选出693个差异表达基因，富集于PI3K-Akt、NF-κB等与肿瘤恶性进展相关的信号通路；RT-qPCR实验证实短链酰基辅酶A合成酶家族成员1（acyl-CoA synthetase short-chain family member 1，ACSS1）、表皮生长因子（epidermal growth factor，EGF）等基因表达下调，钙黏蛋白1（E-cadherin，CDH1)、超氧化物歧化酶2（superoxide dismutase 2，SOD2）等基因表达上调。ChIP-PCR实验证实HDAC3可直接结合于CDH1、SOD2基因的启动子区域，GEO数据集GSE31519分析显示HDAC3与CDH1、SOD2的表达呈显著负相关，且CDH1、SOD2低表达与TNBC患者不良预后相关。结论 HDAC3可通过抑制抑癌基因CDH1、SOD2的转录促进TNBC细胞的增殖、迁移、侵袭及EMT进程，HDAC3有望成为TNBC治疗的潜在分子靶点。

关键词: 三阴性乳腺癌, 组蛋白去乙酰化酶 3, 上皮－间充质转化, 细胞增殖, 细胞迁移, 细胞侵袭

Abstract: Objective To investigate the role of histone deacetylase 3 (HDAC3) in the epithelial-mesenchymal transition (EMT) of triple-negative breast cancer (TNBC) cells and elucidate its underlying mechanisms. Methods The expression level of HDAC3 in breast cancer tissues was analyzed based on Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and immunohistochemical (IHC) staining. The prognostic potential of HDAC3 expression in TNBC patients was analyzed by using Kaplan-Meier Plotter. Cell proliferation was assessed via growth curve and colony formation assays; Transwell assays were performed to evaluate cell migration and invasion. Western blotting analysis was applied to determine the expression of EMT-related markers. RNA-sequencing (RNA-seq) was performed on MDA-MB-231 cells with HDAC3 knockdown to identify target genes and signaling pathways regulated by HDAC3. Key candidate genes were validated by using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). Chromatin immunoprecipitation polymerase chain reaction (ChIP-PCR) was used to verify HDAC3 binding to the promoters of target genes. Finally, the expression correlation between HDAC3 and target genes, along with their clinical prognostic significance, were analyzed by using GEO, TCGA databases and Kaplan-Meier Plotter. Results HDAC3 was significantly upregulated in TNBC tissues, and its elevated expression was closely correlated with poor overall survival (OS) and recurrence-free survival (RFS) in patients. Growth curve, colony formation, and Transwell assays demonstrated that HDAC3 overexpression significantly promoted the proliferation, migration, and invasion of TNBC cells. HDAC3 overexpression downregulated the expression of epithelial markers α-catenin and γ-catenin, while upregulating the expression of mesenchymal markers Fibronectin and Vimentin in MDA-MB-231 and SUM 159 cells, whereas HDAC3 knockdown resulted in the opposite effects. RNA-seq analysis identified 693 differentially expressed genes after HDAC3 knockdown, which were enriched in signaling pathways related to malignant tumor progression, such as the PI3K-Akt and NF-κB pathways. RT-qPCR validation confirmed that the expression of genes including acyl-CoA synthetase short-chain family member 1 (ACSS1) and epidermal growth factor (EGF) was downregulated, while that of genes including E-cadherin (CDH1) and superoxide dismutase 2 (SOD2) was upregulated. ChIP-PCR assays confirmed that HDAC3 could specifically bind to the promoter regions of CDH1 and SOD2. Analysis of the GSE31519 dataset showed that HDAC3 expression was significantly negatively correlated with CDH1 and SOD2 expression. Furthermore, Kaplan-Meier survival analysis revealed that low expression of CDH1 and SOD2 was associated with poor prognosis in TNBC patients. Conclusion HDAC3 promotes the proliferation, migration, invasion, and EMT progression of TNBC cells by through transcriptionally repressing the expression of CDH1 and SOD2. These findings suggest that HDAC3 is a potential therapeutic target for TNBC.

Key words: triple-negative breast cancer, histone deacetylase 3, epithelial-mesenchymal transition, cell proliferation, cell migration, cell invasion

中图分类号:

李情, 王嗣淇, 马天宇, 马枭琪, 孙雨婷, 滕旭, 余和芬, 张竞尧, 黄蔚. 组蛋白去乙酰化酶3促进三阴性乳腺癌细胞上皮－间充质转化的作用和机制研究[J]. 首都医科大学学报, 2026, 47(4): 738-753.

Li Qing#, Wang Siqi#, Ma Tianyu, Ma Xiaoqi, Sun Yuting, Teng Xu, Yu Hefen, Zhang Jingyao△, Huang Wei△. Effect of HDAC3 on promoting the epithelial-mesenchymal transition in triple-negative breast cancer[J]. Journal of Capital Medical University, 2026, 47(4): 738-753.

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组蛋白去乙酰化酶3促进三阴性乳腺癌细胞上皮－间充质转化的作用和机制研究

Effect of HDAC3 on promoting the epithelial-mesenchymal transition in triple-negative breast cancer

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