ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors

Abstract

Histone deacetylase inhibitors (HDACi) are largely ineffective in the treatment of solid tumors. In this study, we describe a new class of protein disulfide isomerase (PDI) inhibitors that significantly and synergistically enhance the anti-tumor activity of HDACi in glioblastoma and pancreatic cancer preclinical models. RNA-seq screening coupled with gene silencing studies identified ATF3 as the driver of this anti-tumor synergy. ATF3 was highly induced by combined PDI and HDACi treatment as a result of increased acetylation of key histone lysine residues (H3K27-ac, H3K18-ac) flanking the ATF3 promoter region. These chromatin marks were associated with increased RNA Polymerase II recruitment to the ATF3 promoter, a synergistic upregulation of ATF3, and a subsequent apoptotic response in cancer cells. The HSP40/HSP70 family genes DNAJB1 and HSPA6 were found to be critical ATF3-dependent genes that elicited the anti-tumor response after PDI and HDAC inhibition. In summary this study presents a synergistic anti-tumor combination of PDI and HDAC inhibitors and demonstrates a mechanistic and tumor suppressive role of ATF3. Combined treatment with PDI and HDAC inhibitors offers a dual therapeutic strategy in solid tumors and the opportunity to achieve previously unrealized activity of HDACi in oncology.