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Ref Type Journal Article
PMID (25612620)
Authors Wang S, Chen XA, Hu J, Jiang JK, Li Y, Chan-Salis KY, Gu Y, Chen G, Thomas C, Pugh BF, Wang Y
Title ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.
Journal Molecular cancer therapeutics
Vol 14
Issue 4
Date 2015 Apr
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
YW3-56 YW3-56 6 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
YW3-56 YW3-56 is a peptidylarginine deiminase (PAD) inhibitor with activity against PAD2 and PAD4, which results in decreased histone citrullination and activation of the endoplasmic reticulum stress response, potentially resulting in decreased tumor cell growth (PMID: 22605338, PMID: 25612620).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown hepatocellular carcinoma not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of a human hepatocellular carcinoma cell line in culture (PMID: 25612620). 25612620
Unknown unknown colorectal cancer not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of colorectal cancer cell lines in culture, independent of TP53 status (PMID: 25612620). 25612620
Unknown unknown Advanced Solid Tumor not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of a variety of human tumor cell lines in culture, independent of TP53 mutational status (PMID: 25612620). 25612620
Unknown unknown osteosarcoma not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of a human osteosarcoma cell line in culture (PMID: 25612620). 25612620
Unknown unknown leukemia not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of human leukemia cell lines in culture, independent of TP53 mutational status (PMID: 25612620). 25612620
Unknown unknown lung carcinoma not applicable YW3-56 Preclinical Actionable In a preclinical study, YW3-56 inhibited proliferation of lung carcinoma cell lines in culture, independent of TP53 status (PMID: 25612620). 25612620