HDAC and Proteasome Inhibitors Synergize to Activate Pro-Apoptotic Factors in Synovial Sarcoma

PLoS One. 2017 Jan 5;12(1):e0169407. doi: 10.1371/journal.pone.0169407. eCollection 2017.

Abstract

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Flow Cytometry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Mice
  • Proteasome Inhibitors / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Sarcoma, Synovial / metabolism*

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Proteasome Inhibitors
  • quisinostat

Grant support

This work was supported by the Canadian Cancer Society Research Institute (Grant # 701582) (http://www.cancer.ca/research/); Terry Fox Research Institute (TFF 105265 New Frontiers in Cancer) (http://www.tfri.ca/en/research/program-project-grants.aspx); The Liddy Shriver Sarcoma Initiative (http://sarcomahelp.org/) and the Sarcoma Cancer Foundation of Canada (Beth England’s Sarcoma Research Fund) (http://sarcomacancer.ca/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.