DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.
In a previous study, we reported that DNA damage induced apoptosis suppressor (DDIAS; hNoxin), a human homolog of mouse Noxin, functions as an anti-apoptotic protein in response to DNA repair. Here we reveal that DDIAS is a target gene of nuclear factor of activated T cells 2 (NFATc1) and is associated with cisplatin resistance in lung cancer cells. In the DDIAS promoter analysis, we found that NFATc1 activated the transcription of DDIAS through binding to NFAT consensus sequences in the DDIAS promoter. In addition, tissue array immunostaining revealed a correlation between DDIAS and NFATc1 expression in human lung tumors. NFATc1 knockdown or treatment with the NFAT inhibitor cyclosporine A induced apoptosis and led to growth inhibition of lung cancer cells, indicating the functional relevance of both the proteins. In contrast, DDIAS overexpression overcame this NFATc1 knockdown-induced growth inhibition, supporting the cancer-specific role of DDIAS as a target gene of NFATc1. NFATc1 or DDIAS inhibition clearly enhanced apoptosis induced by cisplatin in NCI-H1703 and A549 cells. Conversely, DDIAS overexpression rescued NCI-H1703 cells from cisplatin-mediated cell death and caspase-3/7 activation. These results suggest that NFATc1-induced DDIAS expression contributes to cisplatin resistance, and targeting DDIAS or NFATc1 impairs the mechanism regulating cisplatin resistance in lung cancer cells. Taken together, DDIAS is a target of NFATc1 and is associated with cisplatin resistance in lung cancer cells.
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Joo-Young
JY
Im
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Kang-Woo
KW
Lee
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
Kyoung-Jae
KJ
Won
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Bo-Kyung
BK
Kim
Biomedical Translational Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Hyun Seung
HS
Ban
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea.
Sung-Hoon
SH
Yoon
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Young-Ju
YJ
Lee
Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Young-Joo
YJ
Kim
Dept. of Food Science and Technology, Chungnam National University, Daejon 305-764, Republic of Korea.
Kyung-Bin
KB
Song
Genome Structure Research Center, KRIBB, Daejeon 305-806, Republic of Korea; Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea. Electronic address: misun@kribb.re.kr.
Misun
M
Won
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D016572:Cyclosporine; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D002945:Cisplatin
Apoptosis; Cisplatin resistance; DDIAS; Lung cancer; NFATc1; Transcription