Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor.

Autor: Chasse MH; Van Andel Research Institute, Grand Rapids, MI, USA., Johnson BK; Van Andel Research Institute, Grand Rapids, MI, USA., Boguslawski EA; Van Andel Research Institute, Grand Rapids, MI, USA., Sorensen KM; Van Andel Research Institute, Grand Rapids, MI, USA., Rosien JE; Dartmouth College, Hanover, NH, USA., Kang MH; Texas Tech University Health Sciences Center, Lubbock, TX, USA., Reynolds CP; Texas Tech University Health Sciences Center, Lubbock, TX, USA., Heo L; Van Andel Research Institute, Grand Rapids, MI, USA., Madaj ZB; Van Andel Research Institute, Grand Rapids, MI, USA., Beddows I; Van Andel Research Institute, Grand Rapids, MI, USA., Foxa GE; Van Andel Research Institute, Grand Rapids, MI, USA., Kitchen-Goosen SM; Van Andel Research Institute, Grand Rapids, MI, USA., Williams BO; Van Andel Research Institute, Grand Rapids, MI, USA., Triche TJ Jr; Van Andel Research Institute, Grand Rapids, MI, USA., Grohar PJ; Van Andel Research Institute, Grand Rapids, MI, USA.; The Children's Hospital of Philadelphia, Philadelphia, PA, USA.; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2021 Feb 05; Vol. 13 (2), pp. e12640. Date of Electronic Publication: 2020 Dec 17.
DOI: 10.15252/emmm.202012640
Abstrakt: 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.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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