Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Cancer Cell. 2021 Sep 13;39(9):1262-1278.e7. doi: 10.1016/j.ccell.2021.07.003. Epub 2021 Jul 29.
Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers.
融合转录因子（fusion-TFs）是一类难以治疗的驱动癌蛋白。最近，蛋白质降解已成为靶向这些具有挑战性的癌蛋白的一种策略。然而，调节融合-TF 稳定性的机制通常是未知的。通过 CRISPR-Cas9 筛选，我们发现三肽重复序列含 8 蛋白（TRIM8）是一种 E3 泛素连接酶，可泛素化和降解 Ewing 肉瘤中的驱动融合-TF EWS/FLI。此外，我们发现与 >700 种其他癌细胞系相比，TRIM8 在 Ewing 肉瘤中是一种选择性依赖性。从机制上讲，TRIM8 敲除导致 EWS/FLI 蛋白水平增加，但无法耐受。EWS/FLI 作为 TRIM8 的新功能底物，定义了依赖性的选择性。我们的研究结果表明，融合-TF 蛋白稳定性受到严格调控，并强调融合癌蛋白特异性调节剂作为选择性治疗靶点。这项研究提供了一种可行的策略，可在 Ewing 肉瘤和潜在的其他融合-TF 驱动的癌症中治疗性利用致癌基因过表达。
