title: Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity.
abstract: Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|China-Japan Union Hospital of Jilin University, Jilin, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Fang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
authors.forename: Weining
authors.initials: W
authors.lastname: Yang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Faryal Mehwish
authors.initials: FM
authors.lastname: Awan
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D034622:RNA Interference; D000079962:RNA, Circular; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071316:Forkhead Box Protein O3; C488588:PUMA protein, mouse; D000079962:RNA, Circular; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012313:RNA; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin