ATF3 coordinates anti-tumor synergy between epigenetic drugs and protein disulfide isomerase inhibitors.

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.