Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Cell Biol. 2018 Dec;20(12):1410-1420. doi: 10.1038/s41556-018-0221-1. Epub 2018 Nov 5.
Mammalian SWI/SNF chromatin remodelling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF and a newly characterized non-canonical complex (ncBAF). However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma and malignant rhabdoid tumours, which both exhibit cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the ncBAF subunit, BRD9, rapidly attenuates synovial sarcoma and malignant rhabdoid tumour cell proliferation. Importantly, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites and function in a manner distinct from fusion oncoprotein-bound complexes. Together, these findings unmask the unique targeting and functional roles of ncBAF complexes and present new cancer-specific therapeutic targets.
哺乳动物的 SWI/SNF 染色质重塑复合物存在于三种不同的最终形态组装体中：典型的 BAF（cBAF）、PBAF 和新鉴定的非典型复合物（ncBAF）。然而，它们在染色质上的特定靶向、功能以及在疾病中的作用在很大程度上仍未得到明确。在这里，我们全面绘制了染色质上的复合物组装图谱，并发现 ncBAF 复合物独特地定位于 CTCF 位点和启动子。我们鉴定出 ncBAF 亚基作为滑膜肉瘤和恶性横纹肌样肿瘤的合成致死靶点，这两种肿瘤都表现出 cBAF 复合物（SMARCB1 亚基）的扰动。ncBAF 亚基 BRD9 的化学和生物耗竭可迅速减弱滑膜肉瘤和恶性横纹肌样肿瘤细胞的增殖。重要的是，在 cBAF 扰动的癌症中，ncBAF 复合物在保留的 CTCF-启动子位点维持基因表达，并以不同于融合癌蛋白结合复合物的方式发挥作用。综上所述，这些发现揭示了 ncBAF 复合物的独特靶向和功能作用，并提出了新的癌症特异性治疗靶点。
