Journal Article

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

Barrott, Jared J., Jones, Kevin B., Yao, Ren Jie, Underhill, T. Michael, Laporte, Aimée N., Nielsen, Torsten O., Poulin, Neal M., Brodin, Bertha A.

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Apoptosis / Bcl-2 protein / BIM protein / Biology and Life Sciences / Blotting, Western / Cancer therapies / Care and treatment / Cell cycle / Cell Line, Tumor / Cell Survival - drug effects / Cytotoxicity / Diagnosis / Drug delivery / Drug screening / Drug Synergism / Drugs / EGR-1 protein / Endoplasmic reticulum / Epigenetic inheritance / Epigenetics / Flow Cytometry / Gene expression / Genetic aspects / Health aspects / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Histones / Humans / Hydroxamic Acids - pharmacology / Inhibition / Inhibitors / Kinases / Lymphoma / Lymphomas / Medical research / Medical screening / Medicine / Medicine and Health Sciences / Metastases / Mice / Multiple myeloma / Oxygen / Phosphorylation / Physiological aspects / Proteasome inhibitors / Proteasome Inhibitors - pharmacology / Proteasomes / Proteins / Reactive oxygen species / Real-Time Polymerase Chain Reaction / Research and Analysis Methods / Sarcoma / Sarcoma, Synovial - metabolism / Sensitizing / Suppressors / Synergism / Synovial sarcoma / Tumor cell lines