American Association for Cancer Research
00085472can194046-sup-234836_3_supp_6350283_qbtlgf.xlsx (43.12 kB)

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

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posted on 2023-03-31, 03:46 authored by Ravyn M. Duncan, Leticia Reyes, Katelyn Moats, Reeder M. Robinson, Sara A. Murphy, Balveen Kaur, Holly A.F. Stessman, Nathan G. Dolloff

The supplementary tables provide a list of antibodies, plasmids, and primer sets that were used throughout the study. They also include gene transcripts from RNA-Seq analysis that show the genomic pathways altered by the combination of PDI and HDAC inhibitors, as well as ATF3-dependent gene transcripts.


South Carolina Center of Biomedical Research Excellence

Redox Balance and Stress Signaling

American Cancer Society



South Carolina Clinical & Translational Research Institute

Medical University of South Carolina




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 antitumor activity of HDACi in glioblastoma and pancreatic cancer preclinical models. RNA-sequencing screening coupled with gene silencing studies identified ATF3 as the driver of this antitumor synergy. ATF3 was highly induced by combined PDI and HDACi treatment as a result of increased acetylation of key histone lysine residues (acetylated histone 3 lysine 27 and histone 3 lysine 18) 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 antitumor response after PDI and HDAC inhibition. In summary, this study presents a synergistic antitumor combination of PDI and HDAC inhibitors and demonstrates a mechanistic and tumor suppressive role of ATF3. Combined treatment with PDI and HDACi offers a dual therapeutic strategy in solid tumors and the opportunity to achieve previously unrealized activity of HDACi in oncology. This study uses a first-in-class PDI inhibitor entering clinical development to enhance the effects of epigenetic drugs in some of the deadliest forms of cancer.