title: The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development.
abstract: Head-to-head gene pairs represent a unique feature of gene organization in eukaryotes, accounting for >10% of genes in the human genome. Identification and functional analysis of such gene pairs is only in its infancy. Recently, we identified PRR11 as a novel cancer-related gene that is implicated in cell cycle and lung cancer. Here we demonstrate that PRR11 is oriented in a head-to-head configuration with its neighboring gene, SKA2. 5'-RACE assay revealed that the intergenic spacer region between the two genes is <500 bp. Serial luciferase reporter assays demonstrated that a minimal 80-bp intergenic region functions as a core bidirectional promoter to drive basal transcription in both the PRR11 and SKA2 orientations. EMSA and ChIP assays demonstrated that NF-Y binds to and directly transactivates the PRR11-SKA2 bidirectional promoter. SiRNA-mediated NF-Y depletion significantly downregulated PRR11 and SKA2 expression. Expression of both PRR11 and SKA2 was significantly upregulated in lung cancer. Expression of the two genes was highly correlated with each other and with NF-Y expression. Remarkably, high expression of both PRR11 and SKA2 was associated with poorer prognosis in lung cancer patients compared with high expression of one gene or low expression of both genes. Knockdown of PRR11 and/or SKA2 remarkably reduced cell proliferation, migration, and invasion in lung cancer cells. Thus, the PRR11-SKA2 bidirectional transcription unit, which is a novel direct target of NF-Y, is essential for the accelerated proliferation and motility of lung cancer cells and may represent a potential target in the diagnosis and/or treatment of human lung cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Chundong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Huali
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yinjiang
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ai
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Fangzhou
authors.initials: F
authors.lastname: Song
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuohku, Chiba 260-8717, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. Electronic address: buyqcn@cqmu.edu.cn.
authors.forename: Youquan
authors.initials: Y
authors.lastname: Bu
mesh_terms: D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000502:physiology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D023081:CCAAT-Binding Factor; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C524815:PRR11 protein, human; D011506:Proteins; C516428:SKA2 protein, human; D004247:DNA
keywords: Bidirectional promoter; Cell cycle; Lung cancer; NF-Y; PRR11; SKA2