Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis [ChIP-seq]

Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors. Overall design: ChIP-seq of H2AK119ub in DMSO and TAK-981 treated SYO-1 cell line

滑膜肉瘤（Synovial sarcoma, SySa）是一种侵袭性软组织肉瘤，亟需开发靶向治疗方案。本研究利用融合蛋白SS18::SSX介导的转录重编程所赋予的特异性脆弱性——该融合蛋白是滑膜肉瘤唯一的致癌驱动因子。为筛选出相较于其他肿瘤细胞系，对滑膜肉瘤细胞存活具有选择性必需性的基因，我们挖掘了癌症依赖性图谱（Cancer-Dependency-Map）数据集。针对候选滑膜肉瘤选择性靶点开展靶向成簇规律间隔短回文重复序列（CRISPR）文库筛选后发现，小泛素样修饰因子2（small ubiquitin-like modifier 2, SUMO2）是体外与体内实验中最显著的依赖性靶点之一。临床阶段小分子SUMO2抑制剂TAK-981可有效抑制细胞增殖与集落形成能力。转录组分析显示，抑制SUMO2可显著逆转由SS18::SSX融合蛋白调控的基因表达程序。进一步研究表明，基因敲除或SUMO2抑制可降低SS18::SSX融合蛋白的整体表达水平与染色质结合占有率，同时伴随组蛋白2A赖氨酸119泛素化（histone 2A lysine 119 ubiquitination, H2AK119ub）水平下调——该表观遗传标记可促进滑膜肉瘤的发病进程。综上，本研究证实SUMO2为滑膜肉瘤中一种全新的选择性脆弱靶点，为软组织肉瘤的靶向治疗提供了新的研究方向。整体设计：在经二甲基亚砜（Dimethyl sulfoxide, DMSO）与TAK-981处理的SYO-1细胞系中开展H2AK119ub的染色质免疫沉淀测序（ChIP-seq）