title: HDAC8, A Potential Therapeutic Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors (MPNST).
abstract: BACKGROUND
  HDAC isoform-specific inhibitors may improve the therapeutic window while limiting toxicities. Developing inhibitors against class I isoforms poses difficulties as they share high homology among their catalytic sites; however, HDAC8 is structurally unique compared to other class I isoforms. HDAC8 inhibitors are novel compounds and have affinity for class I HDAC isoforms demonstrating anti-cancer effects; little is known about their activity in malignant peripheral nerve sheath tumors (MPNST). Recently, we demonstrated anti-MPNST efficacy of HDAC8i in human and murine-derived MPNST pre-clinical models; we now seek to consider the potential therapeutic inhibition of HDAC8 in MPNST.
  
  
  METHODS
  Four Human MPNST cell lines, a murine-derived MPNST cell line, and two HDAC8 inhibitors (PCI-34051, PCI-48012; Pharmacyclics, Inc. Sunnyvale, CA) were studied. Proliferation was determined using MTS and clonogenic assays. Effects on cell cycle were determined via PI FACS analysis; effects on apoptosis were determined using Annexin V-PI FACS analysis and cleaved caspase 3 expression. In vivo growth effects of HDAC8i were evaluated using MPNST xenograft models. 2D gel electrophoresis and mass spectrometry were used to identify potential HDAC8 deacetylation substrates.
  
  
  RESULTS
  HDAC8i induced cell growth inhibition and marked S-phase cell cycle arrest in human and murine-derived MPNST cells. Relative to control, HDAC8i induced apoptosis in both human and murine-derived MPNST cells. HDAC8i exhibited significant effects on MPNST xenograft growth (p=0.001) and tumor weight (p=0.02). Four potential HDAC8 substrate targets were identified using a proteomic approach: PARK7, HMGB1, PGAM1, PRDX6.
  
  
  CONCLUSIONS
  MPNST is an aggressive sarcoma that is notoriously therapy-resistant, hence the urgent need for improved anti-MPNST therapies. HDAC8 inhibition may be useful for MPNST by improving efficacy while limiting toxicities as compared to pan-HDACis.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Kate Lynn J
authors.initials: KL
authors.lastname: Bill
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Hemant Kumar
authors.initials: HK
authors.lastname: Bid
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Braggio
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Dylan
authors.initials: D
authors.lastname: Constantino
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Bethany
authors.initials: B
authors.lastname: Prudner
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Abeba
authors.initials: A
authors.lastname: Zewdu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Kara
authors.initials: K
authors.lastname: Batte
authors.affiliation: Surgery B, Sheba Medical Center, Tel Aviv, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.affiliation: Surgical Oncology, The Ohio State University, Columbus, OH, United States of America.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009442:Neurilemmoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C409470:HDAC8 protein, human; C000603105:HDAC8 protein, mouse; D006655:Histone Deacetylases