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Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors.

Publication ,  Journal Article
Hedrick, E; Crose, L; Linardic, CM; Safe, S
Published in: Mol Cancer Ther
September 2015

The two major types of rhabdomyosarcoma (RMS) are predominantly diagnosed in children, namely embryonal (ERMS) and alveolar (ARMS) RMS, and patients are treated with cytotoxic drugs, which results in multiple toxic side effects later in life. Therefore, development of innovative chemotherapeutic strategies is imperative, and a recent genomic analysis suggested the potential efficacy of reactive oxygen species (ROS)-inducing agents. Here, we demonstrate the efficacy of the potent histone deacetylase (HDAC) inhibitors, panobinostat and vorinostat, as agents that inhibit RMS tumor growth in vivo, induce apoptosis, and inhibit invasion of RD and Rh30 RMS cell lines. These effects are due to epigenetic repression of cMyc, which leads to decreased expression of cMyc-regulated miRs-17, -20a, and -27a; upregulation of ZBTB4, ZBTB10, and ZBTB34; and subsequent downregulation of Sp transcription factors. We also show that inhibition of RMS cell growth, survival and invasion, and repression of Sp transcription factors by the HDAC inhibitors are independent of histone acetylation but reversible after cotreatment with the antioxidant glutathione. These results show a novel ROS-dependent mechanism of antineoplastic activity for panobinostat and vorinostat that lies outside of their canonical HDAC-inhibitory activity and demonstrates the potential clinical utility for treating RMS patients with ROS-inducing agents.

Duke Scholars

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

September 2015

Volume

14

Issue

9

Start / End Page

2143 / 2153

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • Sp4 Transcription Factor
  • Sp3 Transcription Factor
  • Sp1 Transcription Factor
  • Rhabdomyosarcoma
  • Reactive Oxygen Species
  • Oncology & Carcinogenesis
  • Humans
  • Histone Deacetylase Inhibitors
 

Citation

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Hedrick, E., Crose, L., Linardic, C. M., & Safe, S. (2015). Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors. Mol Cancer Ther, 14(9), 2143–2153. https://doi.org/10.1158/1535-7163.MCT-15-0148
Hedrick, Erik, Lisa Crose, Corinne M. Linardic, and Stephen Safe. “Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors.Mol Cancer Ther 14, no. 9 (September 2015): 2143–53. https://doi.org/10.1158/1535-7163.MCT-15-0148.
Hedrick, Erik, et al. “Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors.Mol Cancer Ther, vol. 14, no. 9, Sept. 2015, pp. 2143–53. Pubmed, doi:10.1158/1535-7163.MCT-15-0148.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

September 2015

Volume

14

Issue

9

Start / End Page

2143 / 2153

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transcription Factors
  • Sp4 Transcription Factor
  • Sp3 Transcription Factor
  • Sp1 Transcription Factor
  • Rhabdomyosarcoma
  • Reactive Oxygen Species
  • Oncology & Carcinogenesis
  • Humans
  • Histone Deacetylase Inhibitors