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Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

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 3 out of 8 mice.

SUBMITTER: Mrs. Maggie, H Chasse

PROVIDER: S-SCDT-EMM-2020-12640 | biostudies-other |

REPOSITORIES: biostudies-other

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Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor.

Project 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.

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Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells.

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SWI/SNF inhibition leads to epigenetic reprogramming in rhabdoid tumor

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-16 | GSE137404 | GEO

Case-based review: atypical teratoid/rhabdoid tumor.

Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.

| S-EPMC6656328 | biostudies-literature

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming.

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Histone deacetylase inhibitor panobinostat induces antitumor activity in epithelioid sarcoma and rhabdoid tumor by growth factor receptor modulation.

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Clinical and Molecular Differentiation Between Malignant Rhabdoid Tumor of the Kidney and Normal Tissue: A Two-Case Report.

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| S-EPMC8042314 | biostudies-literature

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