TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma.
TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma.
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DOI：
10.1016/j.ccell.2021.07.003
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发表时间：
2021-09-13
期刊：
影响因子：
50.3
通讯作者：
Stegmaier K
中科院分区：
文献类型：
--
作者：
Seong BKA;Dharia NV;Lin S;Donovan KA;Chong S;Robichaud A;Conway A;Hamze A;Ross L;Alexe G;Adane B;Nabet B;Ferguson FM;Stolte B;Wang EJ;Sun J;Darzacq X;Piccioni F;Gray NS;Fischer ES;Stegmaier K
融合转录因子（fusion-TF）代表一类难以治疗靶向的驱动癌蛋白。最近，蛋白质降解已成为靶向这些具有挑战性的癌蛋白的策略。然而，调节融合TF稳定性的机制通常是未知的。使用CRISPR-Cas9筛选，我们发现了包含三重基序的8（TRIM 8）作为E3泛素连接酶，其泛素化并降解EWS/FLI，EWS/FLI是尤文肉瘤中的驱动融合TF。此外，与>700种其他癌细胞系相比，我们将TRIM 8鉴定为尤文肉瘤中的选择性依赖性。从机制上讲，TRIM 8敲除导致EWS/FLI蛋白水平的增加，这是不耐受的。EWS/FLI作为TRIM 8的新变体底物，定义了依赖性的选择性。我们的研究结果表明，融合TF蛋白的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易于处理的策略，以治疗尤文肉瘤和其他可能的融合TF驱动的癌症中的癌基因过量。E3连接酶TRIM 8在尤文肉瘤中是一种精确的选择性依赖性TRIM 8调节EWS/FLI表达，但不是其野生型对应物K334对于TRIM 8介导的EWS/FLI降解至关重要增加的EWS/FLI水平诱导尤文肉瘤细胞中的细胞死亡使用CRISPR-Cas9筛选，Seong et al.证明E3连接酶TRIM 8降解尤文肉瘤细胞中的EWS/FLI融合癌蛋白。与>700个非尤文癌模型相比，TRIM 8的敲除在尤文肉瘤中是选择性致死的。TRIM 8缺失增加EWS/FLI蛋白水平，这对尤文肉瘤细胞是有毒的。
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. The E3 ligase TRIM8 is an exquisitely selective dependency in Ewing sarcoma TRIM8 regulates EWS/FLI expression but not its wild-type counterparts K334 is critical for TRIM8-mediated degradation of EWS/FLI Increased EWS/FLI levels induce cell death in Ewing sarcoma cells Using CRISPR-Cas9 screens, Seong et al. demonstrate that the E3 ligase TRIM8 degrades the EWS/FLI fusion oncoprotein in Ewing sarcoma cells. Knockout of TRIM8 is selectively lethal in Ewing sarcoma compared with >700 non-Ewing cancer models. TRIM8 loss increases EWS/FLI protein levels, which is toxic to Ewing sarcoma cells.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
DOI：
10.1073/pnas.1110946108
发表时间：
2011-11-29
影响因子：
11.1
作者：
Li, Qi;Yan, Jie;Wang, Yan-Yi
通讯作者：
Wang, Yan-Yi
影响因子：
64.8
作者：
Gorthi A;Romero JC;Loranc E;Cao L;Lawrence LA;Goodale E;Iniguez AB;Bernard X;Masamsetti VP;Roston S;Lawlor ER;Toretsky JA;Stegmaier K;Lessnick SL;Chen Y;Bishop AJR
通讯作者：
Bishop AJR
影响因子：
30.8
作者：
Dharia NV;Kugener G;Guenther LM;Malone CF;Durbin AD;Hong AL;Howard TP;Bandopadhayay P;Wechsler CS;Fung I;Warren AC;Dempster JM;Krill-Burger JM;Paolella BR;Moh P;Jha N;Tang A;Montgomery P;Boehm JS;Hahn WC;Roberts CWM;McFarland JM;Tsherniak A;Golub TR;Vazquez F;Stegmaier K
通讯作者：
Stegmaier K
DOI：
10.1038/s41571-018-0113-0
发表时间：
2018-12
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Cocco E;Scaltriti M;Drilon A
通讯作者：
Drilon A