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TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer

Oncogene volume 37, pages 2165–2180 (2018)Cite this article

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Abstract

Prostate cancer growth is promoted by the gene regulatory action of androgen receptor (AR) and its downstream signals. The aberrant dysfunction of tumor suppressor p53 has an important role in the prognosis of cancer. We previously found that androgen treatments translocate p53 to the cytoplasm. The mechanism of this translocation depends on sumoylation of p53 by complex of SUMO E3 ligase RanBP2 with androgen-induced GTPase-activating protein-binding protein 2 (G3BP2). Here, we identified tripartite motif-containing protein 25 (TRIM25)/estrogen-responsive finger protein (Efp) as a novel interacting partner of G3BP2 protein complex. Then, we demonstrated that TRIM25 knockdown resulted in p53 downstream activation for cell cycle inhibition and apoptosis induction in LNCaP and 22Rv1 cells. In contrast, overexpression of TRIM25 promoted prostate cancer cell proliferation and inhibited apoptosis by docetaxel treatment in LNCaP cells. We observed that p53 activity was reduced by mechanism of G3BP2-mediated nuclear export in TRIM25-overexpressing prostate cancer cells. We also found TRIM25 is important for G3BP2/RanBP2-mediated p53 modification. Clinically, we newly demonstrated that TRIM25 is a prognostic factor for prostate cancer patients. Expression of TRIM25 is significantly associated with cytoplasmic p53 expression and G3BP2. Moreover, TRIM25 knockdown results in reduced tumor growth and increased p53 activity in the mouse xenograft model of prostate cancer. Thus, our findings show that overexpression of TRIM25 promoted prostate cancer cell proliferation and cell survival by modulating p53 nuclear export mechanism with G3BP2 interaction.

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Acknowledgements

This work was supported by grants of the P-DIRECT and the P-CREATE from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to SI); grants from the Japan Society for the Promotion of Science, Japan (to KT, grant 15K15581; to SI, grant 15K15353); a grant of the Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation, Japan (to SI); Grants-in-Aid (to SI) from the Ministry of Health, Labor and Welfare, Japan, and grants from the Takeda Science Foundation (to SI and KT), the Terumo foundation for Life Sciences and Arts (to KT) and the NOVARTIS Foundation for the Promotion of Science (to KT), Japan.

Author contributions

KT designed the study, performed experiments and analyzed data. TS performed IHC analysis. TT analyzed data. TF and ST prepared and analyzed tumor samples. TU and KI provided important materials such as plasmids and siRNAs. SI supervised the study. KT and SI wrote the manuscript.

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Authors and Affiliations

  1. Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, Japan

    Ken-ichi Takayama & Satoshi Inoue

  2. Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

    Takashi Suzuki

  3. Department of Clinical Cell Biology and Division of Endocrinology and Metabolism, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan

    Tomoaki Tanaka

  4. Department of Urology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Tetsuya Fujimura

  5. Department of Urology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan

    Satoru Takahashi

  6. Department of Geriatric Medicine, International University of Health and Welfare, Narita, Chiba, Japan

    Tomohiko Urano

  7. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama, Japan

    Kazuhiro Ikeda & Satoshi Inoue

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  1. Ken-ichi Takayama
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Correspondence to Satoshi Inoue.

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Takayama, Ki., Suzuki, T., Tanaka, T. et al. TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer. Oncogene 37, 2165–2180 (2018). https://doi.org/10.1038/s41388-017-0095-x

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