Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis

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 andr...

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Published in:Cellular signalling 2014-12, Vol.26 (12), p.2940-2950
Main Authors: Wei, Tong-You Wade, Hsia, Jiun-Yi, Chiu, Shao-Chih, Su, Li-Jen, Juan, Chi-Chang, Lee, Yuan-Chii Gladys, Chen, Jo-Mei Maureen, Chou, Hsiang-Yun, Huang, Jiao-Ying, Huang, Hiang-Ming, Yu, Chang-Tze Ricky
Format: Article
Language:English
Subjects:
Activated
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
AKT
Androgen
Androgens - metabolism
Animals
Cancer
Carcinogenesis - metabolism
Cell Line, Tumor
Cell Movement - genetics
Cell Proliferation
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - pathology
Estrogen
Estrogen Receptor alpha - metabolism
Estrogens
Estrogens - metabolism
G2 Phase
Gene Expression Regulation, Neoplastic
Humans
Inhibitors
Kinases
Lung Neoplasms - genetics
Lung Neoplasms - pathology
MEP50
Methylation
Mice, Inbred BALB C
Mice, Nude
Migration
Neoplasm Proteins - metabolism
Phosphatidylinositol 3-Kinases - metabolism
PI3K
PRMT5
Protein-Arginine N-Methyltransferases - metabolism
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Androgen - metabolism
Signal Transduction
Transforms
Up-Regulation
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Summary: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. •MEP50 promotes cell transforming activities of lung cancer cell lines with limited ER or AR activity.•MEP50 transforms 293T cells which do not express ER and AR.•MEP50 stimulates G2 progression and upregulates CDK1 and cyclin B in 293T.•MEP50 enhances cell migration by adopting Rac1/VASP and FOXA2/Slug/Cadherins cascades in 293T.•MEP50 promotes cell survival by employing PRMT5/PI3K in 293T.
ISSN:0898-6568
1873-3913
DOI:10.1016/j.cellsig.2014.09.014