Group of Childhood Cancer and Blood Disorders, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
Mol Cancer. 2022 Sep 3;21(1):175. doi: 10.1186/s12943-022-01643-4.
Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target.
Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays.
Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo.
We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.
发育过程中的表观遗传编程对于确定细胞谱系至关重要，而这种编程的改变有助于胚胎肿瘤的发生。在神经母细胞瘤中，神经嵴祖细胞阻止其自然分化为交感肾上腺细胞的过程，导致侵袭性和转移性小儿癌症的发展。研究负责致癌表观基因组网络的表观遗传调节剂对于开发针对这些肿瘤的新型表观遗传治疗方法至关重要。哺乳动物转换/蔗糖非发酵（mSWI/SNF）ATP 依赖性染色质重塑复合物在全基因组范围内作用，将表观遗传信号转化为开放染色质状态。本研究旨在了解 mSWI/SNF 对神经母细胞瘤致癌表观基因组的贡献及其作为治疗靶点的潜力。
使用蛋白质组学方法、功能丧失实验、转录组和染色质可及性分析以及体外和体内测定，在神经母细胞瘤细胞中对 mSWI/SNF 复合物进行功能表征。
神经母细胞瘤细胞包含三种主要的 mSWI/SNF 亚型，但只有通过沉默其关键结构亚基 ARID1A 和 ARID1B 破坏 BRG1 相关因子（BAF）复合物，才能通过促进细胞周期阻滞来损害细胞增殖。全基因组染色质重塑和转录组分析显示，BAF 破坏导致广泛的侵袭相关表达程序的表观遗传抑制，涉及整合素、钙粘蛋白和关键间质调节剂，从而减少细胞对细胞外基质的黏附，随后在体外侵袭减少，并极大地抑制神经母细胞瘤转移在体内的起始和生长。
我们报告了 BAF 复合物在维持允许神经母细胞瘤侵袭和转移的表观遗传程序中的一种新型 ATP 酶非依赖性作用，促使开发新的 BAF 药理学结构破坏剂，以用于转移性神经母细胞瘤的治疗。
