Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis.

IF 8.3 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
EMBO Journal Pub Date : 2025-09-01 Epub Date: 2025-08-13 DOI:10.1038/s44318-025-00526-w
Rema Iyer, Anagha Deshpande, Aditi Pedgaonkar, Pramod Akula Bala, Taehee Kim, Gerard L Brien, Darren Finlay, Kristiina Vuori, Alice Soragni, Hiromi I Wetterstein, Rabi Murad, Aniruddha J Deshpande
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引用次数: 0

Abstract

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.

靶向SUMO2逆转由SS18::SSX融合癌蛋白驱动的异常表观遗传重布线,并损害肉瘤发生。
滑膜肉瘤(SySa)是一种侵袭性软组织肉瘤,迫切需要开发靶向治疗。在这里,我们利用了由融合蛋白SS18::SSX (SySa中唯一的致癌驱动因子)的转录重布线所产生的特定漏洞。为了揭示与其他肿瘤细胞系相比,SySa细胞适应性选择性必需的基因,我们挖掘了癌症依赖性图数据。对sysa候选物的靶向CRISPR文库筛选显示,小泛素样修饰物2 (SUMO2)在体外和体内都是最强的依赖性之一。TAK-981是一种临床阶段的小分子SUMO2抑制剂,可有效抑制生长和集落形成能力。转录组学分析显示,SUMO2抑制引发了由SS18::SSX融合策划的基因表达程序的深刻逆转。此外,基因缺失或SUMO2抑制降低了SS18::SSX融合蛋白的全球表达水平和染色质占用,同时降低了组蛋白2A赖氨酸119泛素化(H2AK119ub),这是促进SySa发病的表观遗传标记。综上所述,我们的研究确定了SUMO2在滑膜肉瘤中是一种新的、选择性的易感性,为软组织肿瘤的靶向治疗提供了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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