Sulfiredoxin is an AP-1 target gene that is required for transformation and shows elevated expression in human skin malignancies.
Previous studies have shown that a dominant negative form of c-Jun (TAM67) suppresses mouse skin carcinogenesis both in vitro and in vivo. The current study identifies Sulfiredoxin (Srx) as a unique target of activator protein-1 (AP-1) activation and TAM67 inhibition. Manipulation of Srx levels by ShRNA or over-expression demonstrates that Srx is critical for redox homeostasis through reducing hyperoxidized peroxiredoxins. In JB6 cells, knockdown of Srx abolishes tumor promoter-induced transformation and enhances cell sensitivity to oxidative stress. Knockdown of Srx also impairs c-Jun phosphorylation, implicating a role for Srx in the feedback regulation of AP-1 activity. Screening of patient tissues by tissue microarray reveals elevated Srx expression in several types of human skin cancers. Our study indicates that Srx is a functionally significant target of AP-1 blockade that may have value in cancer prevention or treatment.
Wei
Qiou
Q
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Jiang
Hong
H
Matthews
Connie P
CP
Colburn
Nancy H
NH
D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D003545:Cysteine / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010446:Peptide Fragments / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D010446:Peptide Fragments; D010545:Peroxides; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; C504024:SRXN1 protein, human; D003545:Cysteine