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Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma
Journal article   Open access   Peer reviewed

Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma

Terra Vleeshouwer-Neumann, Michael Phelps, Theo K Bammler, James W MacDonald, Isaac Jenkins and Eleanor Y Chen
PloS one, Vol.10(12), pp.e0144320-e0144320
12/04/2015
DOI: https://doi.org/10.1371/journal.pone.0144320
PMID: 26636678
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https://doi.org/10.1371/journal.pone.0144320View
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Abstract

Down-Regulation - drug effects Ephrin-B1 - biosynthesis Ephrin-B1 - genetics Gene Expression Regulation, Neoplastic - drug effects Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - genetics Histone Deacetylases - metabolism Humans Neoplasm Proteins - genetics Receptor, Notch1 - biosynthesis Receptor, Notch1 - genetics Rhabdomyosarcoma, Embryonal - drug therapy Rhabdomyosarcoma, Embryonal - genetics Rhabdomyosarcoma, Embryonal - metabolism Zebrafish - genetics Zebrafish - metabolism Zebrafish Proteins - antagonists & inhibitors Zebrafish Proteins - biosynthesis Zebrafish Proteins - genetics
Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs) in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP) studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

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