Cargando…
Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor
Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of c...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863405/ https://www.ncbi.nlm.nih.gov/pubmed/33332735 http://dx.doi.org/10.15252/emmm.202012640 |
_version_ | 1783647487369674752 |
---|---|
author | Chasse, Maggie H Johnson, Benjamin K Boguslawski, Elissa A Sorensen, Katie M Rosien, Jessica E Kang, Min H Reynolds, C Patrick Heo, Lyong Madaj, Zachary B Beddows, Ian Foxa, Gabrielle E Kitchen‐Goosen, Susan M Williams, Bart O Triche, Timothy J Grohar, Patrick J |
author_facet | Chasse, Maggie H Johnson, Benjamin K Boguslawski, Elissa A Sorensen, Katie M Rosien, Jessica E Kang, Min H Reynolds, C Patrick Heo, Lyong Madaj, Zachary B Beddows, Ian Foxa, Gabrielle E Kitchen‐Goosen, Susan M Williams, Bart O Triche, Timothy J Grohar, Patrick J |
author_sort | Chasse, Maggie H |
collection | PubMed |
description | Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second‐generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1‐deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM‐defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3‐day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice. |
format | Online Article Text |
id | pubmed-7863405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78634052021-02-16 Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor Chasse, Maggie H Johnson, Benjamin K Boguslawski, Elissa A Sorensen, Katie M Rosien, Jessica E Kang, Min H Reynolds, C Patrick Heo, Lyong Madaj, Zachary B Beddows, Ian Foxa, Gabrielle E Kitchen‐Goosen, Susan M Williams, Bart O Triche, Timothy J Grohar, Patrick J EMBO Mol Med Articles Rhabdoid tumor (RT) is a pediatric cancer characterized by the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. Here we use unbiased screening of cell line panels to identify a heightened sensitivity of rhabdoid tumor to mithramycin and the second‐generation analogue EC8042. The sensitivity of MMA and EC8042 was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1‐deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM‐defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes. Importantly, a single 3‐day infusion of EC8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro to completely cure three out of eight mice. John Wiley and Sons Inc. 2020-12-17 2021-02-05 /pmc/articles/PMC7863405/ /pubmed/33332735 http://dx.doi.org/10.15252/emmm.202012640 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Chasse, Maggie H Johnson, Benjamin K Boguslawski, Elissa A Sorensen, Katie M Rosien, Jessica E Kang, Min H Reynolds, C Patrick Heo, Lyong Madaj, Zachary B Beddows, Ian Foxa, Gabrielle E Kitchen‐Goosen, Susan M Williams, Bart O Triche, Timothy J Grohar, Patrick J Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title | Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title_full | Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title_fullStr | Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title_full_unstemmed | Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title_short | Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
title_sort | mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863405/ https://www.ncbi.nlm.nih.gov/pubmed/33332735 http://dx.doi.org/10.15252/emmm.202012640 |
work_keys_str_mv | AT chassemaggieh mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT johnsonbenjamink mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT boguslawskielissaa mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT sorensenkatiem mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT rosienjessicae mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT kangminh mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT reynoldscpatrick mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT heolyong mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT madajzacharyb mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT beddowsian mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT foxagabriellee mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT kitchengoosensusanm mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT williamsbarto mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT trichetimothyj mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor AT groharpatrickj mithramycininducespromoterreprogramminganddifferentiationofrhabdoidtumor |