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Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

Authors
  • Hoffman, Mariah M.1, 2
  • Zylla, Jessica S.1
  • Bhattacharya, Somshuvra3
  • Calar, Kristin3
  • Hartman, Timothy W.1
  • Bhardwaj, Ratan D.3
  • Miskimins, W. Keith3
  • de la Puente, Pilar3, 4, 5
  • Gnimpieba, Etienne Z.1, 2
  • Messerli, Shanta M.1, 2, 3
  • 1 (E.Z.G.)
  • 2 Department of Biomedical Engineering, University of South Dakota, BioSNTR, Sioux Falls, SD 57107, USA
  • 3 (P.P.)
  • 4 Department of Surgery, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA
  • 5 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57006, USA
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
Mar 23, 2020
Volume
12
Issue
3
Identifiers
DOI: 10.3390/cancers12030756
PMID: 32210076
PMCID: PMC7140080
Source
PubMed Central
Keywords
License
Green

Abstract

Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC’s) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC’s and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including SOX2 . Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo.

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