title: ZBP-89 reduces histone deacetylase 3 by degrading IkappaB in the presence of Pin1.
abstract: BACKGROUND
  Histone deacetylase 3 (HDAC3) is overexpressed in cancers and its inhibition enhances anti-tumor chemotherapy. ZBP-89, a transcription factor, can induce pro-apoptotic Bak and reduce HDAC3 but the mechanism is unknown. Pin1, a molecular switch that determines the fate of phosphoproteins, is known to interact with HDAC3. The aim of this study was to investigate the mechanism how ZBP-89 downregulated HDAC3.
  
  
  METHODS
  In this study, liver cells, Pin1-knockout Pin1(-/-) and Pin1 wild-typed Pin(+/+) cells were used to explore how ZBP-89 reduced HDAC3. The overexpression of ZBP-89 was achieved by infecting cells with Ad-ZBP-89, an adenoviral construct containing ZBP-89 gene. The role of NF-κB was determined using CAY10576, MG132 and SN50, the former two being inhibitors of IκB degradation and SN50 being an inhibitor of p65/p50 translocation. A xenograft tumor model was used to confirm the in vitro data.
  
  
  RESULTS
  ZBP-89 reduced HDAC3, and it could form a complex with IκB and induce IκB phosphorylation to inhibit IκB. Furthermore, ZBP-89-mediated HDAC3 reduction was suppressed by IκB degradation inhibitors CAY10576 and MG132 but not by p65/p50 translocation inhibitor SN50, indicating that IκB decrease rather than the elevated activity of NF-κB contributed to HDAC3 reduction. ZBP-89-mediated HDAC3 or IκB reduction was significantly less obvious in Pin1(-/-) cells compared with Pin1(+/+) cells. In Ad-ZBP-89-infected Pin1(+/+) cancer cells, Pin1 siRNA increased HDAC3 but decreased Bak, compared with cells without ZBP-89 infection. These findings indicate that Pin1 participates in ZBP-89-mediated HDAC3 downregulation and Bak upregulation. The cell culture result was confirmed by in vivo mouse tumor model experiments.
  
  
  CONCLUSIONS
  ZBP-89 attenuates HDAC3 by increasing IκB degradation. Such attenuation is independent of NF-κB activity but partially depends on Pin1. The novel pathway identified may help generate new anti-cancer strategy by targeting HDAC3 and its related molecules.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, NT, P. R. China. mailcaiguo@yahoo.com.cn.|Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, NT, P. R. China. mailcaiguo@yahoo.com.cn.|Sino-America Cancer Research Institute, The Guangdong Medical College, Dongguan, Guangdong province, P R China. mailcaiguo@yahoo.com.cn.
authors.forename: Cai Guo
authors.initials: CG
authors.lastname: Ye
authors.affiliation: Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, NT, P. R. China. 94025769@qq.com.|Department of Hepatobiliary and Pancreas Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China. 94025769@qq.com.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, NT, P. R. China. gchen@cuhk.edu.hk.|Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, NT, P. R. China. gchen@cuhk.edu.hk.
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, NT, P. R. China. huang.glen@gmail.com.
authors.forename: Xiao Lin
authors.initials: XL
authors.lastname: Tang
authors.affiliation: Sino-America Cancer Research Institute, The Guangdong Medical College, Dongguan, Guangdong province, P R China. zhiweihe688@yahoo.com.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: He
authors.affiliation: Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong, NT, P. R. China. hemingliang99@gmail.com.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, NT, P. R. China. paullai@surgery.cuhk.edu.hk.
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D020672:I-kappa B Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D000099186:Histone Deacetylase 3; C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; C110951:ZNF148 protein, human; C491741:Zfp148 protein, mouse; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse