Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

Autor: Maggie H Chasse, Benjamin K Johnson, Elissa A Boguslawski, Katie M Sorensen, Jessica E Rosien, Min H Kang, C Patrick Reynolds, Lyong Heo, Zachary B Madaj, Ian Beddows, Gabrielle E Foxa, Susan M Kitchen‐Goosen, Bart O Williams, Timothy J Triche, Patrick J Grohar
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 2, Pp 1-21 (2020)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202012640
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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