title: Class I and class II histone deacetylases are potential therapeutic targets for treating pancreatic cancer.
abstract: BACKGROUND
  Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer.
  
  
  METHODS
  HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and γH2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively.
  
  
  RESULTS
  The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells.
  
  
  CONCLUSIONS
  Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors.
authors.affiliation: The State Engineering Laboratory of AIDS Vaccine, College of Life Science, Jilin University, Changchun, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhao
authors.forename: Wenting
authors.initials: W
authors.lastname: Yun
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.forename: Asfar
authors.initials: A
authors.lastname: Azmi
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Guo
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014404:Tubulin; D006655:Histone Deacetylases