Sheng Wen-Yi, Zhu Yue, Liu Shi-Qi, Huang Qi-Yan, Qian Wei-Feng, Cheng Jia-le, Huang Huan-Huan, Wang Wen-Jie, Meng You
Department of Thyroid and Breast Surgery, Nanjing Medical University Affiliated Suzhou Hospital: Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, China.
Department of Medical Oncology, Nanjing Medical University Affiliated Suzhou Hospital: Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, China.
Cell Mol Biol Lett. 2025 Sep 1;30(1):105. doi: 10.1186/s11658-025-00788-6.
Triple-negative breast cancer (TNBC) is the most prevalent and fatal cancer affecting women worldwide. The SWI/SNF complexes exhibit the ability to selectively replace subunits, thereby enabling a wide range of epigenetic functions. As an accessory subunit of this complex, ARID1B is critically involved in modulating chromatin accessibility and transcriptional regulation. Nevertheless, its precise contribution to TNBC pathogenesis remains poorly understood.
ARID1B expression levels in TNBC were detected using immunofluorescence and real-time quantitative polymerase chain reaction (PCR). To investigate ARID1B's biological functions in TNBC, a series of in vitro assays were conducted, complemented by subcutaneous tumor xenograft models. Mass spectrometry analysis was employed to identify ARID1B-interacting proteins, while RNA-sequencing (RNA-seq) was performed to screen downstream target genes regulated by ARID1B. The transcriptional regulatory mechanism of ZNF382 mediated by ARID1B was further validated through dual-luciferase reporter assays and Chromatin immunoprecipitation (ChIP)-qPCR. To determine if ZNF382 knockdown could reverse the cellular effects of ARID1B, SMARCC2, and SMARCB1 inhibition, functional rescue experiments were conducted.
We identified ARID1B as a notable E3 ubiquitin ligase gene associated with breast cancer prognosis, particularly serving as a risk prognostic factor in TNBC. Contrary to its previously reported function as an E3 ubiquitin ligase, we observed that ARID1B transcriptionally represses ZNF382 by forming a novel SWI/SNF complex with SMARCC2 and SMARCB1. This newly assembled complex promotes TNBC proliferation and migration, highlighting a previously unrecognized mechanism of ARID1B in cancer development.
This research enhances the understanding of the intricate roles played by SWI/SNF complex components in TNBC and bridges the gap between the structural specificity of SWI/SNF assembly and the progression of cancer. These findings could potentially unveil novel therapeutic targets for TNBC, thereby advancing the development of more efficacious treatment approaches for this highly aggressive malignancy.
三阴性乳腺癌（TNBC）是全球影响女性的最常见且致命的癌症。SWI/SNF复合物具有选择性替换亚基的能力，从而实现广泛的表观遗传功能。作为该复合物的一个辅助亚基，ARID1B在调节染色质可及性和转录调控中起关键作用。然而，其对TNBC发病机制的确切贡献仍知之甚少。
采用免疫荧光和实时定量聚合酶链反应（PCR）检测TNBC中ARID1B的表达水平。为研究ARID1B在TNBC中的生物学功能，进行了一系列体外实验，并辅以皮下肿瘤异种移植模型。采用质谱分析鉴定与ARID1B相互作用的蛋白，同时进行RNA测序（RNA-seq）以筛选受ARID1B调控的下游靶基因。通过双荧光素酶报告基因实验和染色质免疫沉淀（ChIP）-qPCR进一步验证ARID1B介导的ZNF382的转录调控机制。为确定敲低ZNF382是否能逆转ARID1B、SMARCC2和SMARCB1抑制的细胞效应，进行了功能挽救实验。
我们确定ARID1B是一个与乳腺癌预后相关的重要E3泛素连接酶基因，尤其作为TNBC的一个风险预后因素。与其先前报道的作为E3泛素连接酶的功能相反，我们观察到ARID1B通过与SMARCC2和SMARCB1形成一种新型SWI/SNF复合物转录抑制ZNF382。这种新组装的复合物促进TNBC的增殖和迁移，凸显了ARID1B在癌症发展中一种先前未被认识的机制。
本研究增进了对SWI/SNF复合物成分在TNBC中所起复杂作用的理解，并弥合了SWI/SNF组装的结构特异性与癌症进展之间的差距。这些发现可能揭示TNBC的新治疗靶点，从而推动针对这种高度侵袭性恶性肿瘤的更有效治疗方法的开发。
