Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications

被引：13

作者：

Yu, Le ^{[1
,2
]}

Davis, Ian J. ^{[1
,3
,4
]}

Liu, Pengda ^{[1
,2
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Dept Pediat, Chapel Hill, NC 27599 USA

来源：

CANCERS | 2023年 / 15卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Ewing sarcoma; EWSR1-FLI1; transcriptional regulation; post-translational modifications; targeted therapy; HISTONE DEACETYLASE INHIBITOR; EWS-FLI1 FUSION PROTEIN; N-LINKED GLYCOSYLATION; EWINGS-SARCOMA CELLS; TARGET GENE; TRANSCRIPTIONAL ACTIVITY; MOLECULAR PATHOGENESIS; GENOMIC LANDSCAPE; RNA HELICASE; DNA-BINDING;

D O I：

10.3390/cancers15020382

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Ewing sarcoma is a malignant pediatric bone cancer currently lacking targeted therapy. In the US there are similar to 200 patients diagnosed each year and relapse is associated with resistance to the standard-of-care chemotherapy. Thus, it remains an urgent unmet medical need to develop effective new cures for Ewing sarcoma. It is well-characterized that Ewing sarcoma is largely driven by unique gene fusions, with EWSR1-FLI1 being the most prevalent. In this review, we summarize up-to-date regulatory mechanisms for the onco-fusion protein EWSR1-FLI1 in Ewing sarcoma, including both post-transcriptional and post-translational modifications, to reveal knowledge gaps and propose potential new therapeutic directions. Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although most patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, Ewing sarcoma consists of small round basophilic cells with prominent nuclei marked by expression of surface protein CD99. Genetically, Ewing sarcoma is driven by a fusion oncoprotein that results from one of a small number of chromosomal translocations composed of a FET gene and a gene encoding an ETS family transcription factor, with similar to 85% of tumors expressing the EWSR1::FLI1 fusion. EWSR1::FLI1 regulates transcription, splicing, genome instability and other cellular functions. Although a tumor-specific target, EWSR1::FLI1-targeted therapy has yet to be developed, largely due to insufficient understanding of EWSR1::FLI1 upstream and downstream signaling, and the challenges in targeting transcription factors with small molecules. In this review, we summarize the contemporary molecular understanding of Ewing sarcoma, and the post-transcriptional and post-translational regulatory mechanisms that control EWSR1::FLI1 function.

引用

页数：14