title: The PRR11-SKA2 Bidirectional Transcription Unit Is Negatively Regulated by p53 through NF-Y in Lung Cancer Cells.
abstract: We previously identifiedproline-rich protein 11(PRR11) as a novel cancer-related gene that is implicated in the regulation of cell cycle and tumorigenesis. Our recent study demonstrated thatPRR11and its adjacent gene,kinetochore associated 2(SKA2), constitute a classic head-to-head gene pair that is coordinately regulated by nuclear factor Y (NF-Y). In the present study, we further show that thePRR11-SKA2bidirectional transcription unit is an indirect target of the tumor suppressor p53. A luciferase reporter assay revealed that overexpression of wild typep53, but not mutantp53, significantly represses the basal activity and NF-Y mediated transactivation of thePRR11-SKA2bidirectional promoter. Deletion and mutation analysis of thePRR11-SKA2promoter revealed that p53-mediatedPRR11-SKA2repression is dependent on the presence of functional NF-Y binding sites. Furthermore, a co-immunoprecipitation assay revealed that p53 associates with NF-Y in lung cancer cells, and a chromatin immunoprecipitation assay showed that p53 repressesPRR11-SKA2transcription by reducing the binding amount of NF-Y in thePRR11-SKA2promoter region. Consistently, the ability of p53 to downregulatePRR11-SKA2transcription was significantly attenuated upon siRNA-mediated depletion of nuclear factor Y subunit beta (NF-YB). Notably, lung cancer patients with lower expression of eitherPRR11orSKA2along with wild typep53exhibited the best overall survival compared with others withp53mutation and/or higher expression of eitherPRR11orSKA2. Taken together, our results demonstrate that p53 negatively regulates the expression of thePRR11-SKA2bidirectional transcription unit through NF-Y, suggesting that the inability to repress thePRR11-SKA2bidirectional transcription unit after loss of p53 might contribute to tumorigenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. wytao8899@126.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. wytao8899@126.com.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. wyinying@aliyun.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. wyinying@aliyun.com.
authors.forename: Huali
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. vera21173@163.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. vera21173@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. maggie8818@sina.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. maggie8818@sina.com.
authors.forename: Yinjiang
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. cecilylee@126.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. cecilylee@126.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. yulong.niu@aol.com.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. fzsongcq@163.com.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. fzsongcq@163.com.
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, 1# Yixueyuan Road, Yuzhong District, Chongqing 400016, China. buyqcn@cqmu.edu.cn.|Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. buyqcn@cqmu.edu.cn.
authors.forename: Youquan
authors.initials: Y
authors.lastname: Bu
mesh_terms: D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D023081:CCAAT-Binding Factor; D002868:Chromosomal Proteins, Non-Histone; C524815:PRR11 protein, human; D011506:Proteins; C516428:SKA2 protein, human; D016159:Tumor Suppressor Protein p53
keywords: NF-Y; PRR11; SKA2; bidirectional promoter; lung cancer; p53