Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling

Oncotarget. 2015 Aug 28;6(25):21507-21. doi: 10.18632/oncotarget.4242.

Abstract

Histone acetylation marks have an important role in controlling gene expression and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins and novel inhibitiors of these proteins are currently in clinical development. Inhibitors of HDAC and BET proteins have individually been shown to cause apoptosis and reduce growth of melanoma cells. Here we show that combining the HDAC inhibitor LBH589 and BET inhibitor I-BET151 synergistically induce apoptosis of melanoma cells but not of melanocytes. Induction of apoptosis proceeded through the mitochondrial pathway, was caspase dependent and involved upregulation of the BH3 pro-apoptotic protein BIM. Analysis of signal pathways in melanoma cell lines resistant to BRAF inhibitors revealed that treatment with the combination strongly downregulated anti-apoptotic proteins and proteins in the AKT and Hippo/YAP signaling pathways. Xenograft studies showed that the combination of inhibitors was more effective than single drug treatment and confirmed upregulation of BIM and downregulation of XIAP as seen in vitro. These results support the combination of these two classes of epigenetic regulators in treatment of melanoma including those resistant to BRAF inhibitors.

Keywords: I-BET151; bromodomain; epigenetic; melanoma; panobinostat.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Epigenesis, Genetic
  • Female
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Histone Deacetylase Inhibitors / administration & dosage*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / chemistry
  • Immunohistochemistry
  • Indoles / chemistry
  • Melanocytes / metabolism
  • Melanoma / drug therapy
  • Melanoma / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondria / metabolism
  • Neoplasm Transplantation
  • Panobinostat
  • Phosphoproteins / metabolism*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / metabolism*
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Phosphoproteins
  • Transcription Factors
  • YAP1 protein, human
  • Panobinostat
  • AKT1 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • Histone Deacetylases