title: The HDAC inhibitor LBH589 induces ERK-dependent prometaphase arrest in prostate cancer via HDAC6 inactivation and down-regulation.
abstract: Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest. The LBH589 treatment down-regulated HDAC6 and sustained ERK activation, and contributed to prometaphase arrest. Mechanistically, LBH589 inhibited HDAC6 activity, caused its dissociation from protein phosphatase PP1α, and increased 14-3-3ζ acetylation. Acetylated 14-3-3ζ released its mask effect on serine 259 of c-Raf and serine 216 of Cdc25C subsequent to de-phosphorylation by PP1α, which contributed to ERK activation. Enhanced ERK activity by LBH589 further down-regulated HDAC6 protein levels and sustained ERK activation by free-forward regulation. The sustained Cdc25C and ERK activation resulted in early M-phase (prometaphase) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC-3 cells. This study provides pre-clinical evidence that HDAC6 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation. This study also posits a novel mechanism of HDAC6 participation in regulating the c-Raf-PP1-ERK signaling pathway and contributing to M phase cell-cycle transition.
authors.affiliation: Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Mei-Jen
authors.initials: MJ
authors.lastname: Chuang
authors.forename: Sheng-Tang
authors.initials: ST
authors.lastname: Wu
authors.forename: Shou-Hung
authors.initials: SH
authors.lastname: Tang
authors.forename: Xiang-Me
authors.initials: XM
authors.lastname: Lai
authors.forename: Hsiao-Chu
authors.initials: HC
authors.lastname: Lai
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Hsu
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Sun
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Sun
authors.forename: Sun-Yran
authors.initials: SY
authors.lastname: Chang
authors.forename: Dah-Shyong
authors.initials: DS
authors.lastname: Yu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Tai-Lung
authors.initials: TL
authors.lastname: Cha
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008297:Male; D000077767:Panobinostat; D011471:Prostatic Neoplasms / Q000473:pathology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D054645:Protein Phosphatase 1; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
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