The HDAC inhibitor LBH589 induces ERK-dependent prometaphase arrest in prostate cancer via HDAC6 inactivation and down-regulation

PLoS One. 2013 Sep 4;8(9):e73401. doi: 10.1371/journal.pone.0073401. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Acetylation / drug effects
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Indoles / pharmacology*
  • M Phase Cell Cycle Checkpoints / drug effects*
  • Male
  • Panobinostat
  • Prostatic Neoplasms / pathology*
  • Protein Phosphatase 1 / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Signal Transduction / drug effects
  • cdc25 Phosphatases / metabolism

Substances

  • 14-3-3 Proteins
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Panobinostat
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Phosphatase 1
  • CDC25C protein, human
  • cdc25 Phosphatases
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases

Grant support

This work was supported by grants from the National Science Council (97-2314-B-016-023-MY3 and 99-2628-B-016-012-MY3) and from the Tri-Service General Hospital Research Foundation (TSGH-C101-009-S02, TSGH-C100-128 and TSGH-C99-012-13-S03), Taiwan, ROC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.