STAT3 regulated ATR via microRNA-383 to control DNA damage to affect apoptosis in A431 cells.
Skin cancer is a major cause of morbidity and mortality worldwide. Mounting evidence shows that exposure of the skin to solar UV radiation results in inflammation, oxidative stress, DNA damage, dysregulation of cellular signaling pathways and immunosuppression thereby resulting in skin cancer. Signal transducer and activator of transcription 3 (STAT3) is well known to function as an anti-apoptotic factor, especially in numerous malignancies, but the relationship between STAT3 activation and DNA damage response in skin cancer is still not fully understood. We now report that STAT3 inhibited DNA damage induced by UV and STAT3 mediated upregulation of GADD45γ and MDC-1 and the phosphorylation of H2AX in UV induced DNA damage. Notably, STAT3 can increase the expression of ATR in A431 cells. Luciferase assay shows that STAT3 activates the transcription of ATR promoter. More importantly, microRNA-383 suppressed ATR expression by targeting 3' (untranslated regions)UTR of ATR in A431 cells, and STAT3 down-regulates the transcription of miR-383 promoter. Thus, these results reveal the new insight that ATR is down-regulated by STAT3-regulated microRNA-383 in A431 cells. Moreover, overexpression of STAT3 enhanced expression of antiapoptosis genes BCL-1 and MCL-1, and depletion of STAT3 sensitized A431 cells to apoptotic cell death following UV. Collectively, these studies suggest that STAT3 may be a potential target for both the prevention and treatment of human skin cancer.
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China; Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
Xing-Hua
XH
Liao
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
Li
L
Zheng
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
Hong-Peng
HP
He
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
De-Liang
DL
Zheng
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
Zhao-Qiang
ZQ
Wei
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China.
Nan
N
Wang
Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China.
Jian
J
Dong
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China. Electronic address: ma_wj@tust.edu.cn.
Wen-Jian
WJ
Ma
Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, 300457, PR China; Institute of Biology and Medicine, Wuhan University of Science and Technology, 430000, PR China. Electronic address: tony@tust.edu.cn.
Tong-Cun
TC
Zhang
D020413:3' Untranslated Regions / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004789:Enzyme Activation; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis; D014466:Ultraviolet Rays / Q000009:adverse effects; D000097642:GADD45 Proteins
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D006657:Histones; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C468783:H2AX protein, human; C579095:MCL1 protein, human; C413163:MDC1 protein, human; C558685:MIRN383 microRNA, human; C494086:STAT3 protein, human; C576597:ATR protein, human
ATR; DNA damage; STAT3; Skin cancer; miR-383