title: The transcription factor c-Fos coordinates with histone lysine-specific demethylase 2A to activate the expression of cyclooxygenase-2.
abstract: Cyclooxygenase-2 (COX-2) is overexpressed in a variety of human epithelial cancers, including lung cancer, and is highly associated with a poor prognosis and a low survival rate. Understanding how COX-2 is regulated in response to carcinogens will offer insight into designing anti-cancer strategies and preventing cancer development. Here, we analyzed COX-2 expression in several human lung cancer cell lines and found that COX-2 expression was absent in the H719 and H460 cell lines by a DNA methylation-independent mechanism. The re-expression of COX-2 was observed after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment in both cell lines. Further investigation found that H3K36 dimethylation was significantly reduced near the COX-2 promoter because histone demethylase 2A (KDM2A) was recruited to the COX-2 promoter after TPA treatment. In addition, the transcription factor c-Fos was found to be required to recruit KDM2A to the COX-2 promoter for reactivation of COX-2 in response to TPA treatment in both the H719 and H460 cell lines. Together, our data reveal a novel mechanism by which the carcinogen TPA activates COX-2 expression by regulating H3K36 dimethylation near the COX-2 promoter.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Lu
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Du
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Cao
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Meiting
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Changchun
authors.initials: C
authors.lastname: Shen
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Tianyun
authors.initials: T
authors.lastname: Hou
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Beijing 100142, China.
authors.forename: Dajun
authors.initials: D
authors.lastname: Deng
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center of Medical and Health Analysis, Peking University Health Science Center, Beijing 100871, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.|Peking University-Tsinghua University Joint Center for Life Sciences, Beijing 100751, China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
mesh_terms: D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D044783:F-Box Proteins; D016760:Proto-Oncogene Proteins c-fos; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate
keywords: COX-2; KDM2A; c-Fos; histone methylation