title: Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors.
abstract: 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.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Erik
authors.initials: E
authors.lastname: Hedrick
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
authors.forename: Lisa
authors.initials: L
authors.lastname: Crose
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Linardic
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas. Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas. ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D014157:Transcription Factors; D051705:Sp3 Transcription Factor