ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells

  • Mol Cancer Ther. 2015 Apr;14(4):877-88. doi: 10.1158/1535-7163.MCT-14-1093-T.
Shu Wang  1 ,  Xiangyun Amy Chen  1 ,  Jing Hu  1 ,  Jian-Kang Jiang  2 ,  Yunfei Li  1 ,  Ka Yim Chan-Salis  1 ,  Ying Gu  1 ,  Gong Chen  3 ,  Craig Thomas  2 ,  B Franklin Pugh  1 ,  Yanming Wang  4
Affiliations
  • 1. Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
  • 2. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
  • 3. Department of Chemistry, Pennsylvania State University, State College, Pennsylvania.
  • 4. Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania. [email protected].
PMID: 25612620 DOI: 10.1158/1535-7163.MCT-14-1093-T
Abstract

We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit Cancer growth. However, the p53-independent Anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, high-resolution genomic binding sites of ATF4 and CEBPB responsive to YW3-56 treatment were generated. In human breast Cancer cells, YW3-56-mediated cell death features mitochondria depletion and Autophagy perturbation. Moreover, YW3-56 treatment effectively inhibits the growth of triple-negative breast Cancer xenograft tumors in nude mice. Taken together, we unveiled the Anticancer mechanisms and therapeutic potentials of the pan-PAD inhibitor YW3-56.

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