PUBLICATION
Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma
- Authors
- Vleeshouwer-Neumann, T., Phelps, M., Bammler, T.K., MacDonald, J.W., Jenkins, I., Chen, E.Y.
- ID
- ZDB-PUB-170214-67
- Date
- 2015
- Source
- PLoS One 10: e0144320 (Journal)
- Registered Authors
- Keywords
- Cancer treatment, Cell differentiation, Differentiated tumors, Gene expression, Chromatin immunoprecipitation, Histones, Carcinogenesis, Zebrafish
- MeSH Terms
-
- Animals
- 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/biosynthesis*
- 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
- PubMed
- 26636678 Full text @ PLoS One
Citation
Vleeshouwer-Neumann, T., Phelps, M., Bammler, T.K., MacDonald, J.W., Jenkins, I., Chen, E.Y. (2015) Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma. PLoS One. 10:e0144320.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping