title: HDAC Inhibition for the Treatment of Epithelioid Sarcoma: Novel Cross Talk Between Epigenetic Components.
abstract: Epithelioid sarcoma is a rare neoplasm uniquely comprised of cells exhibiting both mesenchymal and epithelial features. Having propensity for local and distant recurrence, it poses a diagnostic dilemma secondary to pathologic complexity. Patients have dismal prognosis due to lack of effective therapy. HDAC inhibitors (HDACi) exhibit marked antitumor effects in various malignancies. The studies here demonstrate that pan-HDAC inhibitors constitute novel therapeutics versus epithelioid sarcoma. Human ES cells (VAESBJ, HS-ES, Epi-544) were studied in preclinical models to evaluate HDACi effects. Immunoblot and RT-PCR were used to evaluate expression of acetylated tubulin, histones H3/H4, EZH2 upon HDACi. MTS and clonogenic assays were used to assess the impact of HDACi on cell growth. Cell culture assays were used to evaluate the impact of HDACi and EZH2-specific siRNA inhibition on cell-cycle progression and survival. Unbiased gene array analysis was used to identify the impact of HDACi on epithelioid sarcoma gene expression. Xenografts were used to evaluate epithelioid sarcoma tumor growth in response to HDACi. HDAC inhibition increased target protein acetylation and abrogated cell growth and colony formation in epithelioid sarcoma cells. HDACi induced G(2) cell-cycle arrest and marked apoptosis, and reduced tumor growth in xenograft models. HDACi induced widespread gene expression changes, and EZH2 was significantly downregulated. EZH2 knockdown resulted in abrogated cell growth in vitro.
  
  
  CONCLUSIONS
  The current study suggests a clinical role for HDACi in human epithelioid sarcoma, which, when combined with EZH2 inhibitors, could serve as a novel therapeutic strategy for epithelioid sarcoma patients. Future investigations targeting specific HDAC isoforms along with EZH2 may potentially maximizing treatment efficacy.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.affiliation: Department of Neurosurgery, Guiyang 300 Hospital, Zunyi Medical College, Guizhou, China.
authors.forename: Yechun
authors.initials: Y
authors.lastname: Song
authors.affiliation: GRU-UGA Medical Partnership, Georgia Regents University, Athens, Georgia.
authors.forename: Ryan
authors.initials: R
authors.lastname: Lam
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dennis
authors.initials: D
authors.lastname: Ruder
authors.affiliation: Department of Medicine and Dan L. Duncan Division of Biostatistics, Baylor College of Medicine, Houston, Texas. Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Hemant Kumar
authors.initials: HK
authors.lastname: Bid
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Kate Lynn
authors.initials: KL
authors.lastname: Bill
authors.affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Surgery B, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, Ohio. raphael.pollock@osumc.edu.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014404:Tubulin