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.
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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 Üren, Jeffrey A Toretsky |
Journal | Nucleic acids research
(Nucleic Acids Res)
Vol. 47
Issue 18
Pg. 9619-9636
(10 10 2019)
ISSN: 1362-4962 [Electronic] England |
PMID | 31392992
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. |
Chemical References |
- ARID1A protein, human
- BANF1 protein, human
- DNA-Binding Proteins
- EWS-FLI fusion protein
- Nuclear Proteins
- Oncogene Proteins, Fusion
- Protein Isoforms
- Proto-Oncogene Protein c-fli-1
- RNA-Binding Protein EWS
- Transcription Factors
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Topics |
- Alternative Splicing
(genetics)
- Carcinogenesis
(genetics)
- Cell Line, Tumor
- Chromatin Assembly and Disassembly
(genetics)
- DNA-Binding Proteins
(chemistry, genetics)
- Epigenesis, Genetic
(genetics)
- Gene Expression Regulation, Neoplastic
- Humans
- Nuclear Proteins
(chemistry, genetics)
- Oncogene Proteins, Fusion
(chemistry, genetics)
- Protein Isoforms
(chemistry, genetics)
- Protein Stability
- Proto-Oncogene Protein c-fli-1
(chemistry, genetics)
- RNA-Binding Protein EWS
(chemistry, genetics)
- Sarcoma, Ewing
(genetics, pathology)
- Transcription Factors
(chemistry, genetics)
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