Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism
| Autor: | Taylor R. Nicholas, Peter C. Hollenhorst |
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| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
0303 health sciences medicine.drug_class Breakpoint EWING SARCOMA BREAKPOINT REGION 1 Biology urologic and male genital diseases medicine.disease Androgen Androgen receptor Fusion gene 03 medical and health sciences Prostate cancer 0302 clinical medicine 030220 oncology & carcinogenesis medicine Cancer research Sarcoma biology.gene 030304 developmental biology |
| DOI: | 10.1101/2020.03.25.008391 |
| Popis: | SummaryEwing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5’ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5’ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5’ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to early transcription termination and breakpoint formation. |
| Databáze: | OpenAIRE |
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