SPOP and OTUD7A Control EWS–FLI1 Protein Stability to Govern Ewing Sarcoma Growth. Issue 14 (1st June 2021)

• Record Type: Journal Article
• Authors: Su, Siyuan; Chen, Jianfeng; Jiang, Yao; Wang, Ying; Vital, Tamara; Zhang, Jiaming; Laggner, Christian; Nguyen, Kong T.; Zhu, Zhichuan; Prevatte, Alex W.; Barker, Natalie K.; Herring, Laura E.; Davis, Ian J.; Liu, Pengda
• Is Part Of: Advanced science. Volume 8:Issue 14(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-01
• Subjects: 7Ai -- CK1 -- Ewing sarcoma -- EWS–FLI1 -- OTUD7A -- SPOP; Science -- Periodicals; 505
• DOI: 10.1002/advs.202004846
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Chromosomal translocation results in development of an Ewing sarcoma breakpoint region 1‐Friend leukemia integration 1 ( EWS–FLI1 ) fusion oncogene in the majority of Ewing sarcoma. The persistent dependence of the tumor for this oncoprotein points to EWS–FLI1 as an ideal drug target. Although EWS–FLI1 transcriptional targets and binding partners are evaluated, the mechanisms regulating EWS–FLI1 protein stability remain elusive. Speckle‐type POZ protein ( SPOP ) and OTU domain‐containing protein 7A ( OTUD7A ) are identified as the bona fide E3 ligase and deubiquitinase, respectively, that control EWS–FLI1 protein turnover in Ewing sarcoma. Casein kinase 1 ‐mediated phosphorylation of the VTSSS degron in the FLI1 domain enhances SPOP activity to degrade EWS–FLI1 . Opposing this process, OTUD7A deubiquitinates and stabilizes EWS–FLI1 . Depletion of OTUD7A in Ewing sarcoma cell lines reduces EWS–FLI1 protein abundance and impedes Ewing sarcoma growth in vitro and in mice. Performing an artificial‐intelligence‐based virtual drug screen of a 4‐million small molecule library, 7Ai is identified as a potential OTUD7A catalytic inhibitor. 7Ai reduces EWS–FLI1 protein levels and decreases Ewing sarcoma growth in vitro and in a xenograft mouse model. This study supports the therapeutic targeting of OTUD7A as a novel strategy for Ewing sarcoma bearing EWS–FLI1 and related fusions, and may also be applicable to other cancers dependent on aberrant FLI1 expression. Abstract : The fusion oncogene Ewing sarcoma breakpoint region 1‐Friend leukemia integration 1 ( EWS–FLI1 ) drives Ewing sarcoma tumorigenesis. This work identifies Speckle‐type POZ protein ( SPOP ) and OTU domain‐containing protein 7A ( OTUD7A ) as the E3 ligase and deubiquitinase, respectively, that regulate EWS–FLI1 protein homeostasis. 7Ai, a putative OTUD7A catalytic inhibitor identified through virtual compound screening, reduces Ewing sarcoma cell growth and migration.