EWS-FLI1 Modulated Alternative Splicing of ARID1A Reveals Novel Oncogenic Function Through the BAF Complex

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2019 Aug 9

PMID 31392992

Citations 33

Authors

Saravana P Selvanathan

Garrett T Graham

Alexander R Grego

Tabari M Baker

J Robert Hogg

Mark Simpson

Mona Batish

Brian Crompton

Kimberly Stegmaier

Eleni M Tomazou

Heinrich Kovar

Aykut Uren

Jeffrey A Toretsky

Affiliations

Soon will be listed here.

Abstract

Connections between epigenetic reprogramming and transcription or splicing create novel mechanistic networks that can be targeted with tailored therapies. Multiple subunits of the chromatin remodeling BAF complex, including ARID1A, play a role in oncogenesis, either as tumor suppressors or oncogenes. Recent work demonstrated that EWS-FLI1, the oncogenic driver of Ewing sarcoma (ES), plays a role in chromatin regulation through interactions with the BAF complex. However, the specific BAF subunits that interact with EWS-FLI1 and the precise role of the BAF complex in ES oncogenesis remain unknown. In addition to regulating transcription, EWS-FLI1 also alters the splicing of many mRNA isoforms, but the role of splicing modulation in ES oncogenesis is not well understood. We have identified a direct connection between the EWS-FLI1 protein and ARID1A isoform protein variant ARID1A-L. We demonstrate here that ARID1A-L is critical for ES maintenance and supports oncogenic transformation. We further report a novel feed-forward cycle in which EWS-FLI1 leads to preferential splicing of ARID1A-L, promoting ES growth, and ARID1A-L reciprocally promotes EWS-FLI1 protein stability. Dissecting this interaction may lead to improved cancer-specific drug targeting.

Citing Articles

Unlocking epigenetics for precision treatment of Ewing's sarcoma.

Fan Z, Dong S, Wang N, Khawar M, Wang J, Sun H Chin J Cancer Res. 2024; 36(3):322-340.

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The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes.

Gimeno-Valiente F, Lopez-Rodas G, Castillo J, Franco L Cancers (Basel). 2024; 16(11).

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Effects of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in patients with osteosarcoma and their influencing factors.

Ding S, Xiong S, Wang X, Zhang C, Chen S, Sun M Clin Transl Oncol. 2024; 26(6):1459-1466.

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PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas.

Mancarella C, Morrione A, Scotlandi K Int J Mol Sci. 2023; 24(22).

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Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.

Gong H, Xue B, Ru J, Pei G, Li Y Cancers (Basel). 2023; 15(16).

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References

Batish M, Raj A, Tyagi S . Single molecule imaging of RNA in situ. Methods Mol Biol. 2011; 714:3-13. DOI: 10.1007/978-1-61779-005-8_1. View

Chansky H, Hu M, Hickstein D, Yang L . Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein. Cancer Res. 2001; 61(9):3586-90. View

Toretsky J, Wright P . Assemblages: functional units formed by cellular phase separation. J Cell Biol. 2014; 206(5):579-88. PMC: 4151146. DOI: 10.1083/jcb.201404124. View

Van Rechem C, Boulay G, Leprince D . HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A. Biochem Biophys Res Commun. 2009; 385(4):586-90. DOI: 10.1016/j.bbrc.2009.05.115. View

Hodges C, Kirkland J, Crabtree G . The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer. Cold Spring Harb Perspect Med. 2016; 6(8). PMC: 4968166. DOI: 10.1101/cshperspect.a026930. View

Kovar H . Blocking the road, stopping the engine or killing the driver? Advances in targeting EWS/FLI-1 fusion in Ewing sarcoma as novel therapy. Expert Opin Ther Targets. 2014; 18(11):1315-28. DOI: 10.1517/14728222.2014.947963. View

Markey F, Ruezinsky W, Tyagi S, Batish M . Fusion FISH imaging: single-molecule detection of gene fusion transcripts in situ. PLoS One. 2014; 9(3):e93488. PMC: 3968151. DOI: 10.1371/journal.pone.0093488. View

Riggi N, Knoechel B, Gillespie S, Rheinbay E, Boulay G, Suva M . EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell. 2014; 26(5):668-681. PMC: 4492343. DOI: 10.1016/j.ccell.2014.10.004. View

Spahn L, Siligan C, Bachmaier R, Schmid J, Aryee D, Kovar H . Homotypic and heterotypic interactions of EWS, FLI1 and their oncogenic fusion protein. Oncogene. 2003; 22(44):6819-29. DOI: 10.1038/sj.onc.1206810. View

10.

Stanton B, Hodges C, Calarco J, Braun S, Ku W, Kadoch C . Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet. 2016; 49(2):282-288. PMC: 5373480. DOI: 10.1038/ng.3735. View

11.

Ohali A, Avigad S, Zaizov R, Ophir R, Horn-Saban S, Cohen I . Prediction of high risk Ewing's sarcoma by gene expression profiling. Oncogene. 2004; 23(55):8997-9006. DOI: 10.1038/sj.onc.1208060. View

12.

Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O . Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007; 11(5):421-9. DOI: 10.1016/j.ccr.2007.02.027. View

13.

Helming K, Wang X, Wilson B, Vazquez F, Haswell J, Manchester H . ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med. 2014; 20(3):251-4. PMC: 3954704. DOI: 10.1038/nm.3480. View

14.

Henderson S, Guiliano D, Presneau N, McLean S, Frow R, Vujovic S . A molecular map of mesenchymal tumors. Genome Biol. 2005; 6(9):R76. PMC: 1242211. DOI: 10.1186/gb-2005-6-9-r76. View

15.

Postel-Vinay S, Veron A, Tirode F, Pierron G, Reynaud S, Kovar H . Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet. 2012; 44(3):323-7. DOI: 10.1038/ng.1085. View

16.

Boulay G, Sandoval G, Riggi N, Iyer S, Buisson R, Naigles B . Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain. Cell. 2017; 171(1):163-178.e19. PMC: 6791823. DOI: 10.1016/j.cell.2017.07.036. View

17.

Khan J, Wei J, Ringner M, Saal L, Ladanyi M, Westermann F . Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med. 2001; 7(6):673-9. PMC: 1282521. DOI: 10.1038/89044. View

18.

Linden M, Thomsen C, Grundevik P, Jonasson E, Andersson D, Runnberg R . FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex. EMBO Rep. 2019; 20(5). PMC: 6500973. DOI: 10.15252/embr.201845766. View

19.

Lee C, Hurwitz J . Human RNA helicase A is homologous to the maleless protein of Drosophila. J Biol Chem. 1993; 268(22):16822-30. View

20.

Brown S, Stoilov P, Xing Y . Chromatin and epigenetic regulation of pre-mRNA processing. Hum Mol Genet. 2012; 21(R1):R90-6. PMC: 3459648. DOI: 10.1093/hmg/dds353. View