title: Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis.
abstract: Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of how MEP50 transforms cells, we investigated whether MEP50 could transform cells independent of AR and ER, and clarified whether PRMT5 could contribute to the MEP50-caused tumor formation. Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very low level of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER. Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cell migration, and activated the cell migration pathways such as Ras-related C3 botulinum toxin substrate 1 (Rac1)/vasodilator-stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process.
authors.affiliation: Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Nantou 545, Taiwan.
authors.forename: Tong-You Wade
authors.initials: TY
authors.lastname: Wei
authors.affiliation: Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Jiun-Yi
authors.initials: JY
authors.lastname: Hsia
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Shao-Chih
authors.initials: SC
authors.lastname: Chiu
authors.affiliation: Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taoyuan County, Taiwan.
authors.forename: Li-Jen
authors.initials: LJ
authors.lastname: Su
authors.affiliation: Institutes of Physiology and Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Juan
authors.affiliation: Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Chii Gladys
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou 545, Taiwan.
authors.forename: Jo-Mei Maureen
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Institutes of Physiology and Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsiang-Yun
authors.initials: HY
authors.lastname: Chou
authors.affiliation: Department of Applied Chemistry, National Chi Nan University, Puli, Nantou 545, Taiwan.
authors.forename: Jiao-Ying
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Hiang-Ming
authors.initials: HM
authors.lastname: Huang
authors.affiliation: Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Puli, Nantou 545, Taiwan; Department of Applied Chemistry, National Chi Nan University, Puli, Nantou 545, Taiwan. Electronic address: ctyu@ncnu.edu.tw.
authors.forename: Chang-Tze Ricky
authors.initials: CT
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008745:Methylation; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000728:Androgens; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D011484:Protein-Arginine N-Methyltransferases; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; C410798:AR protein, human; C506487:ESR1 protein, human; C400529:PRMT5 protein, human; C478359:WDR77 protein, human; D014157:Transcription Factors
keywords: AKT; Androgen; Estrogen; MEP50; PI3K; PRMT5