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
Open Access
- 23 March 2020
- Vol. 12 (3), 756
- https://doi.org/10.3390/cancers12030756
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.Keywords
Funding Information
- National Institutes of Health (P20GM103620, P20GM103548)
- National Institute of General Medical Sciences (P20GM103443)
- National Science Foundation (DGE-1633213)
- Office of Experimental Program to Stimulate Competitive Research (OIA-1849206)
This publication has 110 references indexed in Scilit:
- SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cellsOncogenesis, 2013
- MELK-Dependent FOXM1 Phosphorylation is Essential for Proliferation of Glioma Stem CellsThe International Journal of Cell Cloning, 2013
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer CellsCancer Cell, 2012
- Metadata matters: access to image data in the real worldThe Journal of cell biology, 2010
- Cancer stem cells from colorectal cancer-derived cell linesProceedings of the National Academy of Sciences of the United States of America, 2010
- Human colon cancer epithelial cells harbour active HEDGEHOG‐GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansionEMBO Molecular Medicine, 2009
- Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemiaNature, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Hedgehog signaling maintains a tumor stem cell compartment in multiple myelomaProceedings of the National Academy of Sciences of the United States of America, 2007