A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18-SSX Induces Canonical BAF Destruction.
A Role for SMARCB1 in Synovial Sarcomagenesis Reveals That SS18-SSX Induces Canonical BAF Destruction.
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DOI：
10.1158/2159-8290.cd-20-1219
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发表时间：
2021-10
期刊：
影响因子：
28.2
通讯作者：
Jones KB
中科院分区：
文献类型：
--
作者：
Li J;Mulvihill TS;Li L;Barrott JJ;Nelson ML;Wagner L;Lock IC;Pozner A;Lambert SL;Ozenberger BB;Ward MB;Grossmann AH;Liu T;Banito A;Cairns BR;Jones KB
SMARCB1 保留在包含 PBAF 和 SS18-SSX 的经典 BAF 复合物中，并引导肿瘤发生滑膜肉瘤，而 SS18-SSX 则促进 CBAF 破坏和 BAF 亚家族（CBAF、PBAF、GBAF）重新平衡。长期以来，人们在滑膜肉瘤中观察到 SMARCB1（也称为 BAF47、INI1、SNF5）蛋白水平降低。在这里，我们发现，小鼠中 Smarcb1 遗传缺失与 SS18-SSX 表达相结合，协同产生侵袭性肿瘤，其组织形态学、转录组和全基因组 BAF 家族复合物分布与单独的 SS18-SSX 不同，表明 SMARCB1 在滑膜肉瘤中的决定性作用。在间充质模型的上皮样肉瘤发生中单独沉默 Smarcb1。在小鼠和人类滑膜肉瘤细胞中，SMARCB1 在 PBAF 和经典 BAF (CBAF) 复合物中被鉴定，并与后者中的 SS18-SSX 结合。人类细胞中 CBAF 成分的重组表达重建了包含相同水平 SMARCB1 的 CBAF 子复合物，无论是否包含 SS18 或 SS18-SSX。在体内，SS18-SSX 表达导致整个复合物 CBAF 降解，随着时间的推移，其他 BAF 家族亚型、PBAF 和 GBAF 复合物的相对患病率增加。因此，SS18-SSX 改变 BAF 亚型水平/平衡和基因组分布，驱动滑膜肉瘤发生。 BAF 成分 SMARCB1 的蛋白质水平在滑膜肉瘤中降低，但发挥着决定性作用，融入 PBAF 和包含 SS18-SSX 的经典 BAF 复合物中。 SMARCB1 水平的降低源于 SS18-SSX 驱动的典型 BAF 的整体复合物降解，同时其他 BAF 家族亚型的丰度相对增加。 参见 Maxwell 和 Hargreaves 的相关评论，第 17 页。第 2375 页2355
SMARCB1 is retained in PBAF and SS18–SSX-containing canonical BAF complexes and directs tumors toward synovial sarcomagenesis, while SS18–SSX promotes CBAF destruction and BAF subfamily (CBAF, PBAF, GBAF) rebalancing. Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18–SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18–SSX alone, indicating a defining role for SMARCB1 in synovial sarcoma. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human synovial sarcoma cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, coincorporated with SS18–SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF subcomplexes that contained equal levels of SMARCB1 regardless of SS18 or SS18–SSX inclusion. In vivo, SS18–SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18–SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis. The protein level of BAF component SMARCB1 is reduced in synovial sarcoma but plays a defining role, incorporating into PBAF and SS18–SSX-containing canonical BAF complexes. Reduced levels of SMARCB1 derive from whole-complex degradation of canonical BAF driven by SS18–SSX, with relative increases in the abundance of other BAF-family subtypes. See related commentary by Maxwell and Hargreaves, p. 2375 This article is highlighted in the In This Issue feature, p. 2355