TY - JOUR
T1 - Molecular mechanisms underlying the effects of the small molecule AMC-04 on apoptosis
T2 - Roles of the activating transcription factor 4-C/EBP homologous protein-death receptor 5 pathway
AU - Kim, So Young
AU - Hwang, Supyong
AU - Choi, Min Kyung
AU - Park, Sojung
AU - Nam, Ky Youb
AU - Kim, Inki
N1 - Funding Information:
This study was supported by a grant from the Bio and Medical Technology Development Program of the National Research Foundation of Korea ( 2017M3A9G7072719 to Inki Kim), and by the intramural research program of ASAN Institute for Life Sciences ( 2018–0512 to Inki Kim).We thank the core facilities of HTS and CPC laboratory in the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center for the use of their shared equipment, services, and expertise.
Funding Information:
This study was supported by a grant from the Bio and Medical Technology Development Program of the National Research Foundation of Korea (2017M3A9G7072719 to Inki Kim), and by the intramural research program of ASAN Institute for Life Sciences (2018?0512 to Inki Kim).We thank the core facilities of HTS and CPC laboratory in the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center for the use of their shared equipment, services, and expertise.
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - The unfolded protein response (UPR) is an emerging target pathway for cancer treatment owing to its ability to induce cell death. In our previous analysis of UPR-modulating small molecules, we had reported that piperazine oxalate derivative compounds (AMC-01–04) are able to promote increased phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2α). In this study, we found that AMC-04 induces apoptotic cell death via the activation of UPR in human breast and liver cancer cells. AMC-04 upregulated the expression of activating transcription factor-4 (ATF4)-C/EBP homologous protein (CHOP) and death receptor 5 (DR5) in cancer cells, as revealed by microarray analysis, small-interference RNA assay, and western blotting. From a mechanistic perspective, cytotoxic UPR pathway activation by AMC-04 is mediated by reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (p38 MAPK) signaling. A chemical informatics approach predicted that AMC-04 modulates histone methyltransferase activity. Based on biochemical analysis, the activity of histone methyltransferases, including SUV39H1, SUV39H2, SETDB1, and EHMT1, was inhibited by AMC-04. Furthermore, chemical inhibition of the identified target proteins induced UPR activation and apoptotic cell death, suggesting that inhibition of histone methyltransferases is a promising strategy for cancer therapy. Taken together, we showed that the small molecule AMC-04 modulates epigenetic enzyme activity and mediates the link between cytotoxic UPR and histone modifications.
AB - The unfolded protein response (UPR) is an emerging target pathway for cancer treatment owing to its ability to induce cell death. In our previous analysis of UPR-modulating small molecules, we had reported that piperazine oxalate derivative compounds (AMC-01–04) are able to promote increased phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2α). In this study, we found that AMC-04 induces apoptotic cell death via the activation of UPR in human breast and liver cancer cells. AMC-04 upregulated the expression of activating transcription factor-4 (ATF4)-C/EBP homologous protein (CHOP) and death receptor 5 (DR5) in cancer cells, as revealed by microarray analysis, small-interference RNA assay, and western blotting. From a mechanistic perspective, cytotoxic UPR pathway activation by AMC-04 is mediated by reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (p38 MAPK) signaling. A chemical informatics approach predicted that AMC-04 modulates histone methyltransferase activity. Based on biochemical analysis, the activity of histone methyltransferases, including SUV39H1, SUV39H2, SETDB1, and EHMT1, was inhibited by AMC-04. Furthermore, chemical inhibition of the identified target proteins induced UPR activation and apoptotic cell death, suggesting that inhibition of histone methyltransferases is a promising strategy for cancer therapy. Taken together, we showed that the small molecule AMC-04 modulates epigenetic enzyme activity and mediates the link between cytotoxic UPR and histone modifications.
KW - C/EBP homologous Protein
KW - Death receptor-5
KW - Histone methyl transferase
KW - Human cancer cell
KW - Reactive oxygen species
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85094187647&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2020.109277
DO - 10.1016/j.cbi.2020.109277
M3 - Article
C2 - 33007289
AN - SCOPUS:85094187647
SN - 0009-2797
VL - 332
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
M1 - 109277
ER -