Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1.
Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1.
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DOI：
10.1016/j.celrep.2022.110971
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发表时间：
2022-06-14
期刊：
影响因子：
8.8
通讯作者：
Asangani, Irfan A.
中科院分区：
文献类型：
--
作者：
Deng, Qu;Natesan, Ramakrishnan;Cidre-Aranaz, Florencia;Arif, Shehbeel;Liu, Ying;Rasool, Reyaz ur;Wang, Pei;Mitchell-Velasquez, Erick;Das, Chandan Kanta;Vinca, Endrit;Cramer, Zvi;Grohar, Patrick J.;Chou, Margaret;Kumar-Sinha, Chandan;Weber, Kristy;Eisinger-Mathason, T. S. Karin;Grillet, Nicolas;Gruenewald, Thomas;Asangani, Irfan A.
尤文肉瘤(EWS)是一种高度侵袭性的骨和软组织肿瘤，主要影响儿童和青少年。致病基因OncoFusion EWSR1：：FLI1转录因子通过新生增强子协调致癌转录程序来驱动EWS。通过对代表泛癌细胞系、原发癌、转移癌和正常组织的数千个转录本的综合分析，我们确定了一个32基因信号(ESS32[尤文肉瘤特异性32])，将EWS与泛癌区分开来。在ESS32中，编码立体纤毛蛋白的LOXHD1是通过另一个转录起始点表达最高的基因。EWSR1：：FlI1结合上游新生增强子的缺失或沉默会导致Loxhd1短亚型的丢失，改变EWSR1：：FlI1和HIF1α途径基因，导致EWSR1：：FlI1和HIF1 EWSR1：：FlI1途径基因的改变，导致EWS细胞增殖和侵袭能力下降。这些观察表明LOXHD1是EWS转移的生物标志物和决定因素，并为开发针对LOXHD1的药物或细胞疗法治疗这种致命疾病提供了新的途径。邓等人。使用多个转录数据集的综合生物信息学分析和功能分析来确定LOXHD1是EWS中高度特异的EWSR1：：FLI1靶标。LOXHD1沉默导致低氧反应减弱和致瘤性降低。这些结果表明LOXHD1是EWS的生物标志物和潜在的治疗靶点。
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease. Deng et al. use an integrative bioinformatics analysis of multiple transcriptomic datasets and functional assays to identify LOXHD1 as a highly specific EWSR1::FLI1 target in EwS. LOXHD1 silencing results in attenuated hypoxic response and tumorigenicity. These results implicate LOXHD1 as a biomarker and a potential therapeutic target in EwS.
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影响因子：
28.2
作者：
D'Angelo SP;Melchiori L;Merchant MS;Bernstein D;Glod J;Kaplan R;Grupp S;Tap WD;Chagin K;Binder GK;Basu S;Lowther DE;Wang R;Bath N;Tipping A;Betts G;Ramachandran I;Navenot JM;Zhang H;Wells DK;Van Winkle E;Kari G;Trivedi T;Holdich T;Pandite L;Amado R;Mackall CL
通讯作者：
Mackall CL
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
81.5
作者：
Gruenewald, Thomas G. P.;Cidre-Aranaz, Florencia;Dirksen, Uta
通讯作者：
Dirksen, Uta
DOI：
10.1073/pnas.0801073105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Gangwal, Kunal;Sankar, Savita;Lessnick, Stephen L.
通讯作者：
Lessnick, Stephen L.