小柯机器人

近日，美国丹娜-法伯癌症研究所Kimberly Stegmaier及其团队发现，TRIM8调控EWS/FLI癌蛋白来促进尤文肉瘤的生存。2021年7月29日，《癌细胞》杂志在线发表了这项成果。

利用CRISPR-Cas9筛选，研究人员发现TRIM8（tripartite motif-containing 8）是一个E3泛素连接酶，它能泛素化和降解EWS/FLI，这是尤文肉瘤的一个驱动性融合转录因子（fusion-TF）。此外，与其他700多个癌症细胞系相比，研究人员发现TRIM8在尤文肉瘤中具有选择性依赖。从机制上讲，TRIM8的敲除导致EWS/FLI蛋白水平的增加，而这种增加是不能耐受的。EWS/FLI作为TRIM8的新形态底物，这确定了这种依赖的选择性性质。

结果表明，fusion-TF蛋白的稳定性受到严格的调控，并强调融合肿瘤蛋白特异性调节因子是选择性的治疗靶标。这项研究提供了一个可行的策略来治疗性地利用尤文肉瘤和潜在的fusion-TF驱动型癌症中的癌基因过量。

据介绍，fusion-TF代表了一类难以治疗的肿瘤驱动蛋白。最近，蛋白质降解已经成为靶向这些挑战性肿瘤蛋白的一种策略。然而，调节fusion-TF稳定性的机制通常是未知的。

附：英文原文

Title: TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Author: Bo Kyung A. Seong, Neekesh V. Dharia, Shan Lin, Katherine A. Donovan, Shasha Chong, Amanda Robichaud, Amy Conway, Amanda Hamze, Linda Ross, Gabriela Alexe, Biniam Adane, Behnam Nabet, Fleur M. Ferguson, Bjrn Stolte, Emily Jue Wang, Jialin Sun, Xavier Darzacq, Federica Piccioni, Nathanael S. Gray, Eric S. Fischer, Kimberly Stegmaier

Issue&Volume: 2021-07-29

Abstract: 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.

DOI: 10.1016/j.ccell.2021.07.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00380-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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