Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis
| Autor: | Donglim Esther Park, Patrick Trojer, Michael P. Washburn, Joao A. Paulo, Selene K. Swanson, Matthew L. M. Lim, James A. DeCaprio, Prafulla C. Gokhale, Jingwei Cheng, Camille Cushman, Michelle Tillgren, John P. McGrath, Laurence Florens |
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| Rok vydání: | 2020 |
| Předmět: |
ATOH1
0303 health sciences animal structures biology Chemistry Merkel cell carcinoma Merkel cell polyomavirus Cell Biology biology.organism_classification medicine.disease medicine.disease_cause Chromatin Cell biology law.invention 03 medical and health sciences 0302 clinical medicine law 030220 oncology & carcinogenesis Gene expression biology.protein medicine Suppressor Carcinogenesis Transcription factor 030304 developmental biology |
| Zdroj: | Nature Cell Biology. 22:603-615 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/s41556-020-0503-2 |
| Popis: | Merkel cell carcinoma (MCC)-a neuroendocrine cancer of the skin-is caused by the integration of Merkel cell polyomavirus and persistent expression of large T antigen and small T antigen. We report that small T antigen in complex with MYCL and the EP400 complex activates the expression of LSD1 (KDM1A), RCOR2 and INSM1 to repress gene expression by the lineage transcription factor ATOH1. LSD1 inhibition reduces the growth of MCC in vitro and in vivo. Through a forward-genetics CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodelling complex. Changes in gene expression and chromatin accessibility caused by LSD1 inhibition were partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes. Our work provides mechanistic insight into the dependence of MCC on LSD1 and a tumour suppressor role for ncBAF in cancer. |
| Databáze: | OpenAIRE |
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