Qiao Lu, Liang Zenghua, Ma Pengyi, Zhang Shanshan, Sun Cuiyun, Luo Wenjun, Yu Lin
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Laboratory of Molecular Immunology, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.
Front Immunol. 2025 May 22;16:1590368. doi: 10.3389/fimmu.2025.1590368. eCollection 2025.
Triple-negative breast cancer (TNBC), the most lethal breast cancer subtype, demonstrates poor prognosis due to its high rates of metastasis, recurrence, and mortality. The metastatic potential in TNBC patients serves as a critical determinant of clinical outcomes. The high mobility group AT-hook 2 (HMGA2) has emerged as a novel chromatin architectural regulator, its specific role in TNBC metastasis requires further investigation.
We analyzed the expression of HMGA2 in TNBC and non-TNBC patients using Genomic Data Commons (GDC) The Cancer Genome Atlas (TCGA) and immunohistochemistry. The correlation between HMGA2 expression and patient prognosis was assessed using the Kaplan-Meier estimator. The roles of HMGA2 in TNBC metastasis were validated through cell wound healing assay, transwell assay and lung metastatic model. RNA sequencing, chromatin immunoprecipitation, DNA electrophoretic mobility shift, co-immunoprecipitation and chromosome conformation capture assays were applied to identify the mechanisms by how HMGA2 functions as a novel chromatin architectural regulator.
Our study revealed significantly upregulated HMGA2 expression in TNBC patients compared to non-TNBC patients. Kaplan-Meier survival analysis demonstrated a strong association between elevated HMGA2 expression and poor prognosis in TNBC cases. Functional studies showed that HMGA2 downregulation markedly inhibited TNBC metastatic progression. Mechanistic investigations revealed that HMGA2 facilitates TNBC metastasis through transcriptional activation of matrix metalloproteinases (MMPs). Specifically, HMGA2 interacted with lysine acetyltransferase 6A (KAT6A) to mediate histone acetylation at promoter regions. Concurrently, HMGA2 induced chromatin conformation changes to enhance MMPs transcriptional activity.
These findings establish that the HMGA2/KAT6A complex promote MMPs expression to drive TNBC metastasis, identifying novel therapeutic targets for this aggressive malignancy.
三阴性乳腺癌（TNBC）是最具致死性的乳腺癌亚型，因其高转移率、复发率和死亡率而预后较差。TNBC患者的转移潜能是临床结局的关键决定因素。高迁移率族AT钩蛋白2（HMGA2）已成为一种新型的染色质结构调节剂，其在TNBC转移中的具体作用有待进一步研究。
我们使用基因组数据共享库（GDC）的癌症基因组图谱（TCGA）和免疫组织化学分析了TNBC和非TNBC患者中HMGA2的表达。使用Kaplan-Meier估计器评估HMGA2表达与患者预后之间的相关性。通过细胞伤口愈合试验、Transwell试验和肺转移模型验证了HMGA2在TNBC转移中的作用。应用RNA测序、染色质免疫沉淀、DNA电泳迁移率变动、免疫共沉淀和染色体构象捕获试验来确定HMGA2作为新型染色质结构调节剂发挥作用的机制。
我们的研究显示，与非TNBC患者相比，TNBC患者中HMGA2表达显著上调。Kaplan-Meier生存分析表明，TNBC病例中HMGA2表达升高与预后不良密切相关。功能研究表明，HMGA2下调显著抑制TNBC转移进程。机制研究显示，HMGA2通过转录激活基质金属蛋白酶（MMPs）促进TNBC转移。具体而言，HMGA2与赖氨酸乙酰转移酶6A（KAT6A）相互作用，介导启动子区域的组蛋白乙酰化。同时，HMGA2诱导染色质构象变化，以增强MMPs的转录活性。
这些发现证实HMGA2/KAT6A复合物促进MMPs表达以驱动TNBC转移，为这种侵袭性恶性肿瘤确定了新的治疗靶点。
